Unfolded Protein Response: Cause or Consequence of Lipid and Lipoprotein Metabolism Disturbances?

The liver plays a capital role in the control of whole body energy homeostasis through the metabolization of dietary carbohydrates and lipids. However, under excess macronutrient uptake, those pathways overcharge nucleus-to-endoplasmic reticulum (ER) traffic pathways, leading to luminal overload of unfolded proteins which activates a series of adaptive signaling pathways known as unfolded protein response (UPR). The UPR is a central network mechanism for cellular stress adaptation, however far from a global nonspecific all-or-nothing response. Such a complex signaling network is able to display considerable specificity of responses, with activation of specific signaling branches trimmed for distinct types of stimuli. This makes the UPR a fundamental mechanism underlying metabolic processes and diseases, especially those related to lipid and carbohydrate metabolism. Thus, for a better understanding of the role of UPR on the physiopathology of lipid metabolism disorders, the concepts discussed along this chapter will demonstrate how several metabolic derangements activate UPR components and, in turn, how UPR triggers several metabolic adaptations through its component signaling proteins. This dual role of UPR on lipid metabolism will certainly foment the pursuit of an answer for the question: is UPR cause or consequence of lipid and lipoprotein metabolism disturbances?

Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB/c Mice Infected by Leishmania (Leishmania) infantum.

Leishmaniasis is a neglected tropical disease caused by >20 species of the protozoan parasite Leishmania Meglumine antimoniate (Glucantime) is the first-choice drug recommended by the World Health Organization for the treatment of all types of leishmaniasis. However, the mechanisms of action and toxicity of pentavalent antimonials, including genotoxic effects, remain unclear. Therefore, the mechanism by which meglumine antimoniate causes DNA damage was investigated for BALB/c mice infected by Leishmania (Leishmania) infantum and treated with meglumine antimoniate (20 mg/kg for 20 days). DNA damage was analyzed by a comet assay using mouse leukocytes. Furthermore, comet assays were followed by treatment with formamidopyrimidine-DNA glycosylase and endonuclease III, which remove oxidized DNA bases. In addition, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the animals' sera were assessed. To investigate mutagenicity, we carried out a micronucleus test. Our data demonstrate that meglumine antimoniate, as well as L. infantum infection, induces DNA damage in mammalian cells by the oxidation of nitrogenous bases. Additionally, the antileishmanial increased the frequency of micronucleated cells, confirming its mutagenic potential. According to our data, both meglumine antimoniate treatment and L. infantum infection promote oxidative stress-derived DNA damage, which promotes overactivation of the SOD-CAT axis, whereas the SOD-GPx axis is inhibited as a probable consequence of glutathione (GSH) depletion. Finally, our data enable us to suggest that a meglumine antimoniate regimen, as recommended by the World Health Organization, would compromise GPx activity, leading to the saturation of antioxidant defense systems that use thiol groups, and might be harmful to patients under treatment.

Early and sustained exposure to high-sucrose diet triggers hippocampal ER stress in young rats.

Early-life environmental insults have been shown to promote long-term development of chronic non-communicable diseases, including metabolic disturbances and mental illnesses. As such, premature consumption of high-sugar foods has been associated to early onset of detrimental outcomes, whereas underlying mechanisms are still poorly understood. In the present study, we sought to investigate whether early and sustained exposure to high-sucrose diet promotes metabolic disturbances that ultimately might anticipate neurological injuries. At postnatal day 21, weaned male rats started to be fed a standard chow (10 % sucrose, CTR) or a high-sucrose diet (25 % sucrose, HSD) for 9 weeks prior to euthanasia at postnatal day 90. HSD did not alter weight gain and feed efficiency between groups, but increased visceral, non-visceral and brown adipose tissue accumulation. HSD rats demonstrated elevated blood glucose levels in both fasting and fed states, which were associated to impaired glucose tolerance. Peripheral insulin sensitivity did not change, whereas hepatic insulin resistance was supported by increased serum triglyceride levels, as well as higher TyG index values. Assessment of hippocampal gene expression showed endoplasmic reticulum (ER) stress pathways were activated in HSD rats, as compared to CTR. HSD rats had overexpression of unfolded protein response sensors, PERK and ATF6; ER chaperone, PDIA2 and apoptosis-related genes, CHOP and Caspase 3; but decreased expression of chaperone GRP78. Finally, HSD rats demonstrated impaired neuromuscular function and anxious behavior, but preserved cognitive parameters. In conclusion, our data indicate that early exposure to HSD promote metabolic disturbances, which disrupt hippocampus homeostasis and might precociously affect its neurobehavioral functions.

Hippocampal Endoplasmic Reticulum Stress Hastens Motor and Cognitive Decline in Adult Male Rats Sustainedly Exposed to High-Sucrose Diet.

Metabolic dysfunctions, such as hyperglycemia and insulin resistance, have been associated to cognitive impairment and dementia regardless of advanced age, although the underlying mechanisms are still elusive. Thus, this study investigates the deleterious effects of metabolic syndrome (MetS) induced by long-term exposure to a high-sucrose diet on motor and cognitive functions of male adult rats and its relationship with hippocampal endoplasmic reticulum (ER) stress. Weaned Wistar male rats were fed a high-sucrose diet until adulthood (HSD; 6 months old) and compared to both age-matched (CTR; 6 months old) and middle-aged chow-fed rats (OLD; 20 months old). MetS development, serum redox profile, behavioral, motor, and cognitive functions, and hippocampal gene/protein expressions for ER stress pro-adaptive and pro-apoptotic pathways, as well as senescence markers were assessed. Prolonged exposure to HSD induced MetS hallmarked by body weight gain associated to central obesity, hypertriglyceridemia, insulin resistance, and oxidative stress. Furthermore, HSD rats showed motor and cognitive decline similar to that in OLD animals. Noteworthy, HSD rats presented marked hippocampal ER stress characterized by failure of pro-adaptive signaling and increased expression of Chop, p21, and Parp-1 cleavage, markers of cell death and aging. This panorama resembles that found in OLD rats. In toto, our data showed that early and sustained exposure to a high-sucrose diet induced MetS, which subsequently led to hippocampus homeostasis disruption and premature impairment of motor and cognitive functions in adult rats.

Myricetin improves metabolic outcomes but not cognitive deficit associated to metabolic syndrome in male mice.

Myricetin is a flavonol highly prevalent in edible vegetables and fruits, with recognized hypoglycemic and anti-obesity effects, besides great antioxidant capacity. Thus, this study sought to investigate whether myricetin is able to improve metabolic and behavioral outcomes found in monosodium l-glutamate (MSG) obese mice, a model of metabolic syndrome characterized by early hyperinsulinemia associated to obesity, dyslipidemia, hepatic steatosis, anxiety and cognitive deficit. Newborn male mice received MSG (4 mg kg-1 day-1, s.c.) on alternate days during the first 10 days of life for obesity induction, while control pups received equimolar saline solution. From postnatal day 90 to 135, MSG mice were orally treated with myricetin (50 mg kg-1 day-1) or distilled water, while control animals received vehicle. During the last week of treatment, all groups were submitted to behavioral tests: open field maze, elevated plus maze and Morris water maze. At the end of treatment, animals were euthanized for collection of liver, serum and adipose tissue fat pads. Myricetin treatment reduced the elevated serum levels of glucose and triglycerides, typically found in MSG mice, as well as restored peripheral insulin sensitivity and liver steatosis. Moreover, myricetin ameliorated the lack of thigmotaxis and exploratory behavior, but did not improve the cognitive deficit presented by MSG mice. Therefore, this study contributes to the pharmacological validation of myricetin as an affordable and healthy therapeutic adjuvant for the treatment of metabolic syndrome and most of its comorbidities.

Effects of Vitamin C on the Prevention of Ischemia-Reperfusion Brain Injury: Experimental Study in Rats.

BACKGROUND: Reperfusion syndrome after carotid endarterectomy is a complication associated with cerebrovascular self-regulation in a chronically hypoperfused cerebral hemisphere, leading to severe neurological damage. Vitamin C is an important antioxidant in brain metabolism that has shown some neuroprotective actions. OBJECTIVE: To investigate the potential effects of vitamin C on cerebral reperfusion in comparison with placebo (saline) in rats. METHODS: Male Wistar rats were divided into 3 groups: (i) Sham (n = 4), animals exposed to carotid arteries dissection without clamping; (ii) Control (n = 4), animals exposed to carotid arteries dissection without clamping; (ii) Control (n = 4), animals exposed to carotid arteries dissection without clamping; (ii) Control (. RESULTS: Rats treated with vitamin C presented with a similar behavior as compared to the Sham group in all the three tests (p > 0.05), but it was significantly different from controls (p > 0.05), but it was significantly different from controls (p > 0.05), but it was significantly different from controls (. CONCLUSION: In the present study, vitamin C was associated with behavioral and motor preservation as well as decreased cerebral MDA levels after induced cerebral ischemia in rats.

Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a main cause of dementia, accounting for up to 75% of all dementia cases. Pathophysiological processes described for AD progression involve neurons and synapses degeneration, mainly characterized by cholinergic impairment. This feature makes acetylcholinesterase inhibitors (AChEi) the main class of drugs currently used for the treatment of AD dementia phase, among which galantamine is the only naturally occurring substance. However, several plant species producing diverse classes of alkaloids, coumarins, terpenes, and polyphenols have been assessed for their anti-AChE activity, becoming potential candidates for new anti-AD drugs. Therefore, this mini-review aimed to recapitulate last decade studies on the anti-AChE activity of plant species, their respective extracts, as well as isolated compounds. The anti-AChE activity of extracts prepared from 54 plant species pertaining 29 families, as well as 36 isolated compounds were classified and discussed according to their anti-AChE pharmacological potency to highlight the most prominent ones. Besides, relevant limitations, such as proper antioxidant assessment, and scarcity of toxicological and clinical studies were also discussed in order to help researchers out with the bioprospection of potentially new AChEi.

Pharmacotherapeutic follow-up of a patient with multimorbities: experience report / Acompanhamento farmacoterapêutico em paciente com multimorbidades: um relato de experiência / Seguimiento farmacoterapéutico en pacientes con multimorbilidad: informe de una experiencia

Chronic non-communicable diseases are growing global health problems. The objective of this study was to promote pharmaceutical care for a patient with multimorbidities in order to improve its quality of life. A pharmacotherapeutic follow-up was performed using the SOAP method, registered in the form of clinical evolution, along with laboratory tests, anthropometric measurements and application of validated instruments to assess pharmacological adherence, mental health and quality of life. The report deals with a female patient, 55 years old, obese and dyslipidemic, sedentary, hypertensive, diabetic and on the control phase of breast cancer. Self-medication with antibiotics and a proton pump inhibitor was identified. Despite the good pharmacological adherence, the patient had decompensated diabetes, accompanied by dyslipidemia without treatment and interruption of supplements. After pharmacological and non- pharmacological interventions, the patient showed a significant improvement in the reduction of anthropometric measurements and in biochemical parameters. At the end of the follow-up, pharmaceutical care proved to be fundamental in identifying the patient's health problems, contributing to obtain a more rational pharmacotherapy.

As doenças crônicas não transmissíveis são problemas de saúde globais crescentes. O objetivo deste estudo foi promover a assistência farmacêutica a um paciente com multimorbidades, a fim de melhorar sua qualidade de vida. Foi realizado acompanhamento farmacoterapêutico pelo método SOAP e aplicação de instrumentos validados para avaliar adesão farmacológica, saúde mental e qualidade de vida. O relato trata de uma paciente do sexo feminino, 55 anos, obesa e dislipidêmica, sedentária, hipertensa, diabética e em fase de controle do câncer de mama. Foi identificada automedicação com antibióticos e inibidor de bomba de prótons. Apesar da boa adesão farmacológica, a paciente apresentava diabetes descompensado, acompanhada de dislipidemia sem tratamento e interrupção das suplementações. Após intervenções farmacológicas e não farmacológicas, a paciente apresentou melhora significativa na redução das medidas antropométricas e nos parâmetros bioquímicos. Ao final do acompanhamento, a assistência farmacêutica mostrou-se fundamental na identificação dos problemas de saúde do paciente.

Las enfermedades crónicas no transmisibles constituyen un creciente problema de salud mundial. El objetivo de este estudio fue promover la asistencia farmacéutica a un paciente con multimorbilidades para mejorar su calidad de vida. Se realizó seguimiento farmacoterapéutico por el método SOAP y aplicación de instrumentos validados para evaluar adherencia farmacológica, salud mental y calidad de vida. O relato trata de uma paciente do sexo feminino, 55 anos, obesa e dislipidêmica, sedentária, hipertensa, diabética e em fase de controle do câncer de mama. Se identificó automedicación con antibióticos e inhibidor de la bomba de protones. A pesar del buen cumplimiento farmacológico, la paciente presentó diabetes descompensada, acompañada de dislipidemia no tratada e interrupción de la suplementación. Tras intervenciones farmacológicas y no farmacológicas, la paciente mostró una mejoría significativa en la reducción de las medidas antropométricas y los parámetros bioquímicos. Al final del seguimiento, la asistencia farmacéutica demostró ser fundamental en la identificación de los problemas de salud del paciente.

Long-term high-protein diet intake reverts weight gain and attenuates metabolic dysfunction on high-sucrose-fed adult rats.

BACKGROUND: Consumption of added sugars has been considered a worldwide public health concern by its association with metabolic syndrome and its comorbidities. Meanwhile, current studies have suggested high-protein diets to promote weight loss and improved metabolic outcomes. Thus, this study aimed to investigate the effects of long-term high-protein diet (HPD, 34.3% protein) intake on high-sucrose-fed rats. METHODS: Weaned male Wistar rats were randomized into two groups: rats fed a standard chow (CT/CT, 10% sucrose) or rats fed a high-sucrose diet (HSD, 25% sucrose) for a 20-week observational period. Subsequently, HS/HS animals were randomized into 3 new groups: rats maintained on HSD diet (HS/HS); rats submitted to HSD replacement by standard chow (HS/CT); and those with HSD replaced by HPD (HS/HP). All groups were followed up for 12 weeks during which we investigated the effects of HPD on body weight, energy intake, obesity development, glicemic/lipid profile, glucose tolerance, insulin resistance, tissue weight (adipose tissue, liver and skeletal muscles), lipolytic activity, liver lipoperoxidation and histology, as well as serum markers of hepatic function. RESULTS: Post-weaning exposure to HSD led to metabolic syndrome phenotype at adulthood, herein characterized by central obesity, glucose intolerance, dyslipidaemia and insulin resistance. Only HPD feeding was able to revert weight gain and adipose tissue accumulation, as well as restore adipose tissue lipolytic response to sympathetic stimulus. On the other hand, either HPD or withdrawal from HSD promoted very similar metabolic outcomes upon 12-week nutritional intervention. HS/HP and HS/CT rats showed reduced fasting serum levels of glucose, triacylglycerol and total cholesterol, which were correlated with the improvement of peripheral insulin sensitivity, as inferred from kITT and TyG Index values. Both nutritional interventions restored liver morphofunctional patterns, but only HPD restored lipid peroxidation. CONCLUSIONS: Our data showed that 12-week intake of an isocaloric moderately high-protein diet consistently restored high-sucrose-induced central adiposity and obesity in addition to the attenuation of other important metabolic outcomes, such as improvement of glucolipid homeostasis associated to increased insulin sensitivity and reversal of hepatic steatosis. On the other hand, simple withdrawal from high-sucrose consumption also promoted the abovementioned metabolic outcomes with no impact on body weight.

Long-term exposure to high-sucrose diet down-regulates hepatic endoplasmic reticulum-stress adaptive pathways and potentiates de novo lipogenesis in weaned male mice.

Childhood consumption of added sugars, such as sucrose, has been associated to increased risk of metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD). Although the mechanisms underlying NAFLD onset are incompletely defined, recent evidence has proposed a role for the endoplasmic reticulum (ER) stress. Thus, the present study sought to investigate the metabolic outcomes of high-sucrose intake on weaned Swiss mice fed a 25% sucrose diet for 30, 60 and 90 days in comparison to regular chow-fed controls. High-sucrose feeding promoted progressive metabolic and oxidative disturbances, starting from fasting and fed hyperglycemia, hyperinsulinemia, glucose intolerance and increased adiposity at 30-days; passing by insulin resistance, hypertriglyceridemia and NAFLD onset at 60 days; until late hepatic oxidative damage at 90 days. In parallel, assessment of transcriptional and/or translational levels of de novo lipogenesis (DNL) and ER stress markers showed up-regulation of both fatty acid synthesis (ChREBP and SCD1) and oxidation (PPARα and CPT-1α), as well as overexpression of unfolded protein response sensors (IRE1α, PERK and ATF6), chaperones (GRP78 and PDIA1) and antioxidant defense (NRF2) genes at 30 days. At 60 days, fatty acid oxidation genes were down-regulated, and ER stress switched over toward a proapoptotic pattern via up-regulation of BAK protein and CHOP gene levels. Finally, down-regulation of both NRF2 and CPT-1α protein levels led to late up-regulation of SREBP-1c and exponential raise of fatty acids synthesis. In conclusion, our study originally demonstrates a temporal relationship between DNL and ER stress pathways toward MetS and NAFLD development on weaned rats fed a high-sucrose diet.

Acompanhamento farmacoterapêutico no contexto das doenças crônicas e distúrbios menores em uma unidade básica de saúde de São Luís-Ma / Pharmacotherapeutic follow-up in the context of chronic diseases and minor disorders in a basic health unit of São Luís-Ma / Seguimiento farmacoterapéutico en el contexto de enfermedades crónicas y trastornos más pequeños en una unidad de salud básica de São Luís-Ma

As doenças crônicas não transmissíveis (DCNT's) são responsáveis por cerca de 74% da mortalidade global. Nesse contexto, o acompanhamento farmacoterapêutico surge como uma importante ferramenta para garantir uma farmacoterapia racional em prol da melhoria da qualidade de vida do paciente. Levando isso em consideração, este estudo tem como objetivo avaliar o impacto do acompanhamento farmacêutico na qualidade de vida de um paciente idoso com tratamento irracional da hipertensão arterial sistêmica (HAS), diabetes mellitus e outros sintomas da síndrome metabólica. Paciente M.M.D., masculino, 67 anos, hiperglicêmico, dislipidêmico e que se automedicava para hipertensão sem diagnóstico médico com uma série de medicamentos potencialmente inapropriados (PIM's). Após as intervenções farmacêuticas apresentou melhora nos quadros e maior adesão à terapia medicamentosa atrelada a melhores hábitos de vida. Dessa forma, o impacto positivo das intervenções durante o acompanhamento farmacêutico reforça a importância do profissional na atenção básica e na promoção da saúde.

Chronic non-communicable diseases (NCDs) account for about 74% of global mortality. In this context, pharmacotherapeutic follow-up appears to be an important tool for ensuring rational pharmacotherapy in favor of improving the patient's quality of life. Taking this into consideration, this study aims to evaluate the impact of pharmaceutical follow-up on the quality of life of an elderly patient with irrational treatment of systemic arterial hypertension (SAH), diabetes mellitus and other symptoms of metabolic syndrome. M.M.D. patient, male, 67 years old, hyperglycemic, dyslipidemic and self-medicating for hypertension without medical diagnosis with a series of potentially inappropriate medications (PIM's). After the pharmaceutical interventions showed an improvement in the conditions and greater adherence to drug therapy coupled to better habits of life. Thus, the positive impact of interventions during pharmaceutical follow-up reinforces the importance of the professional in basic care and health promotion.

Las enfermedades no transmisibles crónicas representan aproximadamente el 74% de la mortalidad mundial. En este contexto, el seguimiento farmacoterapéutico es una herramienta importante para garantizar una farmacoterapia racional para mejorar la calidad de vida del paciente. Teniendo esto en cuenta, este estudio tiene por objeto evaluar el impacto del seguimiento farmacéutico en la calidad de vida de un paciente de edad avanzada con el tratamiento irracional de la hipertensión arterial sistémica (HAS), la diabetes mellitus y otros síntomas del síndrome metabólico. Paciente con M.M.D. masculino de 67 años de edad, hiperglucemia, dislipidemia y automedicación para la hipertensión sin diagnóstico médico con una serie de medicamentos potencialmente inapropiados (PIMs). Después de las intervenciones farmacéuticas, mostró una mejoría en las tablas y una mayor adherencia a la terapia con medicamentos, junto con mejores hábitos de vida. De esta manera, el impacto positivo de las intervenciones durante el seguimiento farmacéutico refuerza la importancia del profesional en la atención básica y la promoción de la salud.