[Activation of endoplasmic reticulum stress sensors by metabolic disease-associated diets and COVID-19]. / Activación de sensores del estrés del retículo endoplásmico por dietas asociadas a enfermedades metabólicas y COVID-19.

The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identification of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted.

El retículo endoplásmico es un organelo abundante, dinámico y sensor de energía. Sus abundantes membranas, rugosa y lisa, se encuentran distribuidas en diferentes proporciones dependiendo del linaje y requerimiento celular. Su función es llevar a cabo la síntesis de proteínas y lípidos, y es el almacén principal de Ca2+ intracelular. La sobrecarga calórica y la glucolipotoxicidad generada por dietas hipercalóricas provoca la alteración del retículo endoplásmico, activando la respuesta a proteínas mal plegadas (UPR, Unfolded Protein Response, por sus siglas en inglés) como reacción al estrés celular relacionado con el retículo endoplásmico y cuyo objetivo es restablecer la homeostasis del organelo al disminuir el estrés oxidante, la síntesis de proteínas y la fuga de Ca2+. Sin embargo, durante un estrés crónico, la UPR induce formación de especies reactivas de oxígeno, inflamación y apoptosis, exacerbando el estado del retículo endoplásmico y propagando un efecto nocivo para los demás organelos. Es por ello que el estrés del retículo endoplásmico se ha considerado un inductor del inicio y desarrollo de enfermedades metabólicas, incluido el agravamiento de COVID-19. Hasta el momento, existen pocas estrategias para reestablecer la homeostasis del retículo endoplásmico, las cuales son dirigidas a los sensores que desencadenan la UPR. Por tanto, se justifica con urgencia la identificación de nuevos mecanismos y terapias novedosas relacionadas con mitigar el impacto del estrés del retículo endoplásmico y las complicaciones asociadas.

Activación de sensores del estrés del retículo endoplásmico por dietas asociadas a enfermedades metabólicas y COVID-19 / Activation of endoplasmic reticulum stress sensors by metabolic disease-associated diets and COVID-19

El retículo endoplásmico es un organelo abundante, dinámico y sensor de energía. Sus abundantes membranas, rugosa y lisa, se encuentran distribuidas en diferentes proporciones dependiendo del linaje y requerimiento celular. Su función es llevar a cabo la síntesis de proteínas y lípidos, y es el almacén principal de Ca2+ intracelular. La sobrecarga calórica y la glucolipotoxicidad generada por dietas hipercalóricas provoca la alteración del retículo endoplásmico, activando la respuesta a proteínas mal plegadas (UPR, Unfolded Protein Response, por sus siglas en inglés) como reacción al estrés celular relacionado con el retículo endoplásmico y cuyo objetivo es restablecer la homeostasis del organelo al disminuir el estrés oxidante, la síntesis de proteínas y la fuga de Ca2+. Sin embargo, durante un estrés crónico, la UPR induce formación de especies reactivas de oxígeno, inflamación y apoptosis, exacerbando el estado del retículo endoplásmico y propagando un efecto nocivo para los demás organelos. Es por ello que el estrés del retículo endoplásmico se ha considerado un inductor del inicio y desarrollo de enfermedades metabólicas, incluido el agravamiento de COVID-19. Hasta el momento, existen pocas estrategias para reestablecer la homeostasis del retículo endoplásmico, las cuales son dirigidas a los sensores que desencadenan la UPR. Por tanto, se justifica con urgencia la identificación de nuevos mecanismos y terapias novedosas relacionadas con mitigar el impacto del estrés del retículo endoplásmico y las complicaciones asociadas.

The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identif ication of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted.

Clinical experience after tetrafocal intraocular lens implantation "PANOPTIX" / Experiência clínica após implantação de lentes intraoculares tetrafocais "PANOPTIX"

Abstract Purpose: To assess long, intermediate and near uncorrected visual acuity after a tetrafocal diffractive intraocular lens implantation, presence of dystopic phenomenon and patient satisfaction after surgery. Methods: Retrospective, observational study performed in Puerta de Hierro Specialties Hospital, in Jalisco, México. That included 100 eyes after phacoemulsification surgery by femtosecond assistance, followed by tetrafocal diffractive intraocular lens implantation due to cataract. Long, intermediate and near visual acuity without correction was measured, and presence or absence of dystopic phenomenon, plus patient satisfaction after surgery. Results: A total of 100 eyes in 50 patients who underwent cataract surgery with phacoemulsification by femtosecond assistance were evaluated. 100% underwent bilateral phacoemulsification. Long, intermediate, and near visual acuity after three months was in the most patients 20/20 (46%), 20/15 (44%) and Jaeger 1 (48%) respectively. The percentage or patients who refers halos was 7%; and other associated symptoms in 18%, being astenopia the most prevalent. The removal of the lens was not required in any case. Conclusion: Tetrafocal diffractive intraocular lenses provides excellent intermediate vision (at 60 centimeters) and satisfactory near (30 centimeters) and long (6 meters) visual acuity.

Resumo Objetivo: Avaliar a acuidade visual de longe, intermediária e de perto após o implante de lente intra-ocular difrativa tetrafocal, presença de fenômenos distópicos e satisfação do paciente após a cirurgia. Métodos: Estudo retrospectivo, observacional, realizado em Puerta de Hierro Hospital de Especialidades, em Jalisco, México. Isso incluiu 100 olhos após a cirurgia de facoemulsificação pela presença de laser de femtosegundo, seguida por implante de lente intra-ocular difrativa tetrafocal devido à catarata ou cirurgia facorrefractiva. Foi medida a acuidade visual de longe, intermediária e de perto, e a presença ou ausência de fenômenos distópicos, além da satisfação do paciente após a cirurgia. Resultados: Um total de 100 olhos em 50 pacientes submetidos à cirurgia de catarata com facoemulsificação por femtosegundo foram avaliados. 100% foram submetidos a facoemulsificação bilateral. A acuidade visual para longe, intermediária e de perto após três meses foi na maioria dos pacientes 20/20 (46%), 20/15 (44%) e Jaeger 1 (48%) respectivamente. A porcentagem ou pacientes que se referem a halos foi de 7%; e outros sintomas associados em 18%, sendo a astenopia a mais prevalente. A remoção da lente não foi necessária em nenhum caso. Conclusão: A lente intra-ocular difrativa tetrafocal fornece excelente visão intermediária (a 60 centímetros) e acuidade visual satisfatória de perto a (30 centímetros) e de longe (6 metros).

Novel Triamcinolone Acetonide-Loaded Liposomal Topical Formulation Improves Contrast Sensitivity Outcome After Femtosecond Laser-Assisted Cataract Surgery.

Purpose: To assess visual results, macular modifications, and the incidence of clinically significant macular edema (CSME) in patients using a topical triamcinolone acetonide-loaded liposomal formulation (TA-LF) after femtosecond laser-assisted cataract surgery (FLACS). Methods: Fifty-six eyes after FLACS were selected. Twenty-eight eyes in the combined therapy group (P + N) were treated with prednisolone 1% and nepafenac 0.1% for 21 days postoperatively, whereas 28 eyes in the TA-LF group received a liposomal formulation containing 2 mg/mL of TA (0.2%) for the same period of time. Follow-up visits at 1 day, 6 weeks, and 12 weeks after surgery consisted of visual acuity, contrast sensitivity (CS), central foveal thickness (CFT), total macular volume (TMV) measurements, and the detection of CSME. Results: CS improved in the TA-LF group (basal value: 1.087 ± 0.339 vs. 1.276 ± 0.147 at week 12, P = 0.0346), whereas in the P + N group, CS was not different from the baseline (basal value: 1.130 ± 0.331 vs. 1.274 ± 0.133 at week 12, P = 0.1276). There were similar increases in postoperative CFT and TMV in both groups. CFT and TMV significantly correlate with CS only in the TA-LF group. The r2 for CFT and CS was 0.1963 (P = 0.0206), whereas the r2 for TMV and CS was 0.3615 (P = 0.0007) at 12 weeks. No difference was observed in the incidence of CSME between the groups. Conclusion: TA-LF is associated with better CS outcomes compared to combined therapy after FLACS.

Molecular alterations induced by fructose and its impact on metabolic diseases / Alteraciones moleculares inducidas por fructosa y su impacto en las enfermedades metabólicas

Scientific evidence has identified that the excessive consumption of products made from high-fructose corn syrup is a trigger for obesity, whose prevalence increased in recent years. Due to the metabolic characteristics of fructose, a rapid gastric emptying is produced, altering signals of hunger-satiety and decreasing the appetite. In addition to the hepatic level during catabolism, triose phosphate is generated and adenosine triphosphate (ATP) is reduced, producing uric acid. Triose phosphate triggers the synthesis of fatty acids that increase the production and accumulation of triglycerides, diacylglycerols and ceramides that induce insulin resistance. Hyperlipidemia, insulin resistance and hyperuricemia contribute to the development of hypertension, cardiovascular disease, kidney failure, non-alcoholic fatty liver disease and some kinds of cancer. Understanding the molecular mechanisms and signaling pathways altered by the consumption of fructose is relevant to understand the development of metabolic diseases, as well as to seek therapeutic strategies to improve quality of life.

Las evidencias científicas identifican que el excesivo consumo de productos elaborados con jarabe de maíz de alta fructosa es el detonante de la obesidad, cuya prevalencia incrementó en los últimos años. Debido a las características metabólicas de la fructosa, se produce un rápido vaciado gástrico que altera las señales de hambre-saciedad y disminuye el apetito. A nivel hepático, durante su catabolismo se generan triosas fosfato y decrece el trifosfato de adenosina (ATP, por sus siglas en inglés), lo cual produce ácido úrico. Las triosas fosfato son dirigidas hacia la síntesis de ácidos grasos, incrementando la producción y la acumulación de triacilglicéridos, diacilglicerol y ceramidas que inducen resistencia a la insulina. La hiperlipidemia, la resistencia a la insulina y la hiperuricemia contribuyen al desarrollo de hipertensión, enfermedad cardiovascular, enfermedad renal crónica, hígado graso no alcohólico y algunos tipos de cáncer. Entender los mecanismos moleculares y las vías de señalización alteradas por el consumo de fructosa es relevante para comprender el desarrollo de enfermedades metabólicas, así como la búsqueda de estrategias terapéuticas para procurar una mejor calidad de vida.

Nicotinamide, a glucose-6-phosphate dehydrogenase non-competitive mixed inhibitor, modifies redox balance and lipid accumulation in 3T3-L1 cells.

AIMS: Excessive energy uptake of dietary carbohydrates results in their storage as fat and requires glucose-6-phosphate dehydrogenase (G6PD)-mediated NADPH production. We sought to assess whether the nicotinamide-induced reduction of G6PD activity might modulate redox balance and lipid accumulation in 3T3-L1 cells. MAIN METHODS: 3T3-L1 preadipocytes (days 4 and 6 of differentiation) and adipocytes were cultured in the presence of 5 or 25 mM glucose. The cells cultured in 25 mM glucose were supplemented with nicotinamide (5-15 mM). Next, we evaluated the following parameters: cell viability, apoptosis, lipid accumulation, lipolysis, reducing power, reactive oxygen species (ROS), NAD(P)H and NAD(P)(+), isocitrate dehydrogenase (IDP), malic enzyme and G6PD, as well as the protein and mRNA levels of G6PD. We also analysed the kinetics of the nicotinamide-induced inhibition of G6PD. KEY FINDINGS: G6PD mRNA levels increased at day 4 of adipocyte differentiation, whereas G6PD activity progressively increased at days 4 and 6 of differentiation and was reduced in adipocytes. Concomitantly, ROS, reducing power and lipid accumulation increased gradually as the preadipocytes matured into adipocytes. High glucose increased the activity of G6PD, which coincided with an increase in ROS, reducing power and lipid accumulation. All of these changes are prevented by nicotinamide, with the exception of lipid accumulation in adipocytes. Nicotinamide increased IDP activity without affecting NADPH levels. Lastly, nicotinamide inhibited G6PD in a non-competitive mixed way. SIGNIFICANCE: Nicotinamide modulates G6PD via a non-competitive mixed inhibition and decreases high glucose-dependent oxidative stress and lipid accumulation. Nicotinamide maintains NADPH levels by increasing the activity of IDP.

Glucose-6-phosphate dehydrogenase activity and NADPH/NADP+ ratio in liver and pancreas are dependent on the severity of hyperglycemia in rat.

Hyperglycemia is associated with metabolic disturbances affecting cell redox potential, particularly the NADPH/NADP+ ratio and reduced glutathione levels. Under oxidative stress, the NADPH supply for reduced glutathione regeneration is dependent on glucose-6-phosphate dehydrogenase. We assessed the effect of different hyperglycemic conditions on enzymatic activities involved in glutathione regeneration (glucose-6-phosphate dehydrogenase and glutathione reductase), NADP(H) and reduced glutathione concentrations in order to analyze the relative role of these enzymes in the control of glutathione restoration. Male Sprague-Dawley rats with mild, moderate and severe hyperglycemia were obtained using different regimens of streptozotocin and nicotinamide. Fifteen days after treatment, rats were killed and enzymatic activities, NADP(H) and reduced glutathione were measured in liver and pancreas. Severe hyperglycemia was associated with decreased body weight, plasma insulin, glucose-6-phosphate dehydrogenase activity, NADPH/NADP+ ratio and glutathione levels in the liver and pancreas, and enhanced NADP+ and glutathione reductase activity in the liver. Moderate hyperglycemia caused similar changes, although body weight and liver NADP+ concentration were not affected and pancreatic glutathione reductase activity decreased. Mild hyperglycemia was associated with a reduction in pancreatic glucose-6-phosphate dehydrogenase activity. Glucose-6-phosphate dehydrogenase, NADPH/NADP+ ratio and glutathione level, vary inversely in relation to blood glucose concentrations, whereas liver glutathione reductase was enhanced during severe hyperglycemia. We conclude that glucose-6-phosphate dehydrogenase and NADPH/NADP+ were highly sensitive to low levels of hyperglycemia. NADPH/NADP+ is regulated by glucose-6-phosphate dehydrogenase in the liver and pancreas, whereas levels of reduced glutathione are mainly dependent on the NADPH supply.

[Molecular aspects of chronic hyperglycemia-induced tissue damage]. / Aspectos moleculares del daño tisular inducido por la hiperglucemia crónica.

The knowledge of the molecular basis of diabetes mellitus physiopathology will allow improvements in treatment or prevention of the disease. Diabetes mellitus is a complex disease in which hyperglycemia leads to complications in several organs. In this condition, there is increase in reactive oxygen species (ROS) as a result of glucose autooxidation; its metabolism produces accumulation of metabolites such as fructose, sorbitol, and triose phosphate. The latter generates a oxoaldehydes with high capacity to produce protein glycation and oxidative stress. Moreover, there is an increase in synthesis of diacylglycerol from triosephosphate, which activates protein kinase C. On the other hand, alteration of normal ratio between reduced and oxidized niacinamide nucleotides leads to low efficiency of antioxidative systems. Finally, this metabolic dysregulation causes altered signal transduction, abnormal gene expression, and tissue damage, resulting in development of diabetic complications.

Aspectos moleculares del daño tisular inducido por la hiperglucemia crónica / Molecular Aspects of Chronic Hyperglycemia-Induced Tissue Damage

El propósito de este trabajo es dar a conocer las bases moleculares de la fisiopatología de la diabetes mellitus, con el fin de prevenir la enfermedad o mejorar el tratamiento. La diabetes mellitus es una enfermedad compleja, donde la hiperglucemia crónica provoca complicaciones en distintos órganos. En esta condición aumentan las especies reactivas de oxígeno como resultado de su autooxidacción, por lo que su metabolismo propicia la acumulación de metabolitos como la fructosa, el sorbitol y las triosas fosfato. Éstos últimos generan α-oxoaldehídos reactivos con alta capacidad de unirse a proteínas y generar estrés oxidativo. Además, hay aumento de la síntesis de diacilgliceroles a partir de las triosas fosfato, las cuales activan a la pro teína cinasa C. Por otra parte, la alteración de la proporción normal entre los nucleótidos de niacinamida reducidos con respecto a los oxidados conduce a una baja eficiencia de los sistemas antioxidantes. Finalmente, estas desregulaciones metabólicas causan alteración en la transducción de la señal, en la expresión anormal de genes, además de daño tisular, lo que propicia complicaciones en los pacientes con diabetes.

The knowledge of the molecular basis of diabetes mellitus physiopathology will allow improvements in treatment or prevention of the disease. Diabetes mellitus is a complex disease in which hyperglycemia leads to complications in several organs. In this condition, there is increase in reactive oxygen species (ROS) as a result of glucose autooxidation; its metabolism produces accumulation of metabolites such as fructose, sorbitol, and triose phosphate. The latter generates α oxoaldehydes with high capacity to produce protein glycation and oxidative stress. Moreover, there is an increase in synthesis of diacylglycerol from triose phosphate, which activates protein kinase C. On the other hand, alteration of normal ratio between reduced and oxidized niacinamide nucleotides leads to low efficiency of antioxidative systems. Finally, this metabolic dysregulation causes altered signal transduction, abnormal gene expression, and tissue damage, resulting in development of diabetic complications.