Transcription factor EB (TFEB) is considered the master transcriptional regulator of autophagy and lysosomal biogenesis, which regulates target gene expression through binding to CLEAR motifs. TFEB dysregulation has been linked to the development of numerous pathological conditions; however, several other lines of evidence show that TFEB might be a point of convergence of diverse signaling pathways and might therefore modulate other important biological processes such as cellular senescence, DNA repair, ER stress, carbohydrates, and lipid metabolism and WNT signaling-related processes. The regulation of TFEB occurs predominantly at the post-translational level, including phosphorylation, acetylation, SUMOylating, PARsylation, and glycosylation. It is noteworthy that TFEB activation is context-dependent; therefore, its regulation is subjected to coordinated mechanisms that respond not only to nutrient fluctuations but also to stress cell programs to ensure proper cell homeostasis and organismal health. In this review, we provide updated insights into novel post-translational modifications that regulate TFEB activity and give an overview of TFEB beyond its widely known role in autophagy and the lysosomal pathway, thus opening the possibility of considering TFEB as a potential therapeutic target.

Introducción y objetivo El cáncer gástrico es la neoplasia más frecuente del tubo digestivo en todo el mundo. Las tasas de incidencia varían de acuerdo a la región o el país analizado. La variación en diferentes regiones de México es atribuida a patrones alimenticios, ambientales y genéticos muy específicos. El objetivo de este trabajo es realizar un análisis epidemiológico de los casos de cáncer gástrico atendidos en el Hospital Regional de Alta Especialidad «Ciudad Salud», ubicado en Chiapas. Material y métodos Se realizó un estudio descriptivo, ambispectivo, longitudinal. Se analizó la base de datos del servicio de oncología de este hospital y se buscaron los casos de cáncer gástrico en el periodo de 2007 a 2014. Los datos obtenidos se analizaron con el programa estadístico SPSS v.20. Resultados: Se detectaron un total de 100 casos de cáncer gástrico; se incluyeron 84; 41 pertenecían al sexo masculino y 43 al sexo femenino. La edad promedio fue de 57.3 años. Se encontró una incidencia de 2.14 por cada 100 egresos de pacientes de oncología. El 35.71% del total de pacientes refirió haber sido alcohólico y el 22.61% refirió ser fumador. Del total de pacientes, al 90.16% se les diagnosticó adenocarcinoma. Al final del seguimiento, del total de pacientes, 18 habían muerto. Conclusión: Los resultados del presente análisis epidemiológico mostraron que el consumo de alcohol y tabaco tuvo un papel importante en el desarrollo del cáncer gástrico en los pacientes estudiados, así como el tener antecedentes de familiares con cualquier tipo de cáncer. Debido a que el cáncer gástrico generalmente se diagnostica en etapas avanzadas, es razonable que se elabore un plan para la prevención, la detección temprana y el control de esta enfermedad en nuestra región y estado. Introduction and aim Gastic cancer is the most frequent neoplasia of the digestive tract worldwide. Incidence rates vary according to the region or country analyzed. Variation in the different regions of Mexico is attributed to very specific dietary, environmental, and genetic patterns. The aim of the present work was to carry out an epidemiologic analysis of the cases of gastric cancer treated at the Hospital Regional de Alta Especialidad ‘Ciudad Salud’, located in Chiapas, Mexico. Material and methods A descriptive, ambispective, longitudinal study was conducted. Cases of gastric cancer were searched for in the database from the oncology service of our hospital, that were treated within the time frame of 2007 to 2014. The data obtained were analyzed using the SPSS v. 20 statistics program. Results: A total of 100 cases of gastric cancer were detected, 84 of which were included in the study. Forty-one of the cases were men, 43 were women, and their mean age was 57.3 years. Incidence was 2.14 for every 100 oncology patients released from the hospital. Of the study patients, 35.71% stated they had been alcoholics, 22.61% were smokers, and 90.16% were diagnosed with adenocarcinoma. At the end of follow-up, 18 of the study patients had died. Conclusion: The results of the present epidemiologic analysis showed that the consumption of alcohol and tobacco played an important role in the development of gastric cancer in the patients studied, as well as having a family history of any type of cancer. Because gastric cancer is usually diagnosed in advanced stages, it would be reasonable to formulate a strategy for the prevention, early detection, and control of the disease in the State of Chiapas, Mexico.

Some polymorphisms in genes codifying for fibrinogen have been correlated with plasma levels of this protein, and several studies reported their associations with acute cardiovascular events. In the present study, 118 subjects with unstable and stable coronary diseases were enrolled to determinate the associations among fibrinogen gene polymorphisms, plasma fibrinogen levels, and major cardiovascular adverse events in a sample of southwestern Mexico. The groups, including 81 control subjects, were matched for age, sex, body mass index, and sedentarism. Plasma fibrinogen levels and the polymorphisms 455G/A, -148C/T, +1689T/G, andBclI of the gene of fibrinogen were compared in all groups. Plasma fibrinogen levels (>465 mg/dl) were significant in patients with coronary disease.Fibrinogenplasmavalues>450mg/dlwere associated with cardiovascular mortality during the follow-up analysis of the unstable coronary disease group (p=0.04). The allelic loads of -455A and -148T were associated withplasmafibrinogenlevels>450mg/dl(p<0.003andp=0.03, respectively) and with coronary disease (p=0.016andp<0.006, respectively). The follow-up of posterior events after an acute coronary event showed that the genetic load of the -148T allele was associated with major adverse cardiovascular events (RR=1.8,95%CI=1.01‐3.35,p=0.04).Fibrinogenplasmaticlevels>450mg/dland the fibrinogen polymorphisms -455G/A and 148C/T had association with MACE and coronary disease. This study suggests that these gene polymorphisms are associated with cardiovascular risk.

Giardia lamblia is a single-celled eukaryotic parasite with a small genome and is considered an early divergent eukaryote. The pentose phosphate pathway (PPP) plays an essential role in the oxidative stress defense of the parasite and the production of ribose-5-phosphate. In this parasite, the glucose-6-phosphate dehydrogenase (G6PD) is fused with the 6-phosphogluconolactonase (6PGL) enzyme, generating the enzyme named G6PD::6PGL that catalyzes the first two steps of the PPP. Here, we report that the G6PD::6PGL is a bifunctional enzyme with two catalytically active sites. We performed the kinetic characterization of both domains in the fused G6PD::6PGL enzyme, as well as the individual cloned G6PD. The results suggest that the catalytic activity of G6PD and 6PGL domains in the G6PD::6PGL enzyme are more efficient than the individual proteins. Additionally, using enzymatic and mass spectrometry assays, we found that the final metabolites of the catalytic reaction of the G6PD::6PGL are 6-phosphoglucono-δ-lactone and 6-phosphogluconate. Finally, we propose the reaction mechanism in which the G6PD domain performs the catalysis, releasing 6-phosphoglucono-δ-lactone to the reaction medium. Then, this metabolite binds to the 6PGL domain catalyzing the hydrolysis reaction and generating 6-phosphogluconate. The structural difference between the G. lamblia fused enzyme G6PD::6PGL with the human G6PD indicate that the G6PD::6PGL is a potential drug target for the rational synthesis of novels anti-Giardia drugs.

Treatments to combat giardiasis have been reported to have several drawbacks, partly due to the drug resistance and toxicity of current antiparasitic agents. These constraints have prompted many researchers to investigate new drugs that act against protozoan parasites. Enzyme inhibition is an important means of regulating pathogen metabolism and has recently been identified as a significant alternative target in the search for new treatments. Glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase (G6PD::6PGL) is a bifunctional enzyme involved in the pentose phosphate pathway (PPP) in Giardia lamblia (G. lamblia). The G. lamblia enzyme is unusual since, unlike the human enzyme, it is a fused enzyme. Here, we show, through inhibition assays, that an in-house chemical library of 120 compounds and four target compounds, named CNZ-7, CNZ-8, CMC-1, and FLP-2, are potent inhibitors of the G. lamblia G6PD::6PGL fused enzyme. With a constant (k₂) of 2.3, 3.2, and 2.8 M⁻¹ s⁻¹, respectively, they provoke alterations in the secondary and tertiary protein structure and global stability. As a novel approach, target compounds show antigiardial activity, with IC₅₀ values of 8.7, 15.2, 15.3, and 24.1 µM in trophozoites from G. lamblia. Moreover, these compounds show selectivity against G. lamblia, since, through counter-screening in Caco-2 and HT29 human cells, they were found to have low toxicity. This finding positions these compounds as a potential and attractive starting point for new antigiardial drugs.

Helicobacter pylori (H. pylori) has been proposed as the foremost risk factor for the development of gastric cancer. We found that H. pylori express the enzyme glucose-6-phosphate dehydrogenase (HpG6PD), which participates in glucose metabolism via the pentose phosphate pathway. Thus, we hypothesized that if the biochemical and physicochemical characteristics of HpG6PD contrast with the host G6PD (human G6PD, HsG6PD), HpG6PD becomes a potential target for novel drugs against H. pylori. In this work, we characterized the biochemical properties of the HpG6PD from the H.pylori strain 29CaP and expressed the active recombinant protein, to analyze its steady-state kinetics, thermostability, and biophysical aspects. In addition, we analyzed the HpG6PD in silico structural properties to compare them with those of the HsG6PD. The optimal pH for enzyme activity was 7.5, with a T_1/2 of 46.6 °C, at an optimum stability temperature of 37 °C. The apparent K_m values calculated for G6P and NADP⁺ were 75.0 and 12.8 µM, respectively. G6P does not protect HpG6PD from trypsin digestion, but NADP⁺ does protect the enzyme from trypsin and guanidine hydrochloride (Gdn-HCl). The biochemical characterization of HpG6PD contributes to knowledge regarding H. pylori metabolism and opens up the possibility of using this enzyme as a potential target for specific and efficient treatment against this pathogen; structural alignment indicates that the three-dimensional (3D) homodimer model of the G6PD protein from H. pylori is different from the 3D G6PD of Homo sapiens.