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The Western diet (high in fat and sucrose) consumption is a highly prevalent feature in the whole world, mainly due to the increasing consumption of ultra-processed foods (UPF), which are cheaper and easier-to-eat, as compared to fresh and highly nutritive meals. Epidemiological studies have associated UPF consumption with development of obesity, non-alcoholic fat liver disease (NAFLD) and insulin resistance. For molecular studies, mice fed with Western diets have been used to characterize signaling pathways involved in these diet-induced pathologies. However, these studies fed mice continuously with the diets, which is not compatible with what occurs in real life, when consumption is occasional. Here, we fed mice once-a-week with a high fat, high sucrose (HFHS) diet and compared these animals with those fed continuously with HFHS diet or with a standard diet. Our results show that after a single day of consuming HFHS, animals presented impaired oral glucose tolerance test (oGTT) as compared to control group. Although this impairment was reversed after 24 h consuming regular diet, repetition of HFHS consumption once-a-week aggravated the picture such as after 12-weeks, oGTT impairment was not reversed after 6 days under control diet. Liver steatosis, inflammation, impaired insulin signaling pathway and endoplasmic reticulum stress are similar comparing animals that consumed HFHS once-a-week with those that continuously consumed HFHS, though weekly-fed animals did not gain as much weight. Therefore, we conclude that regimen of one day HFHS plus 6 days normal diet over 12 weeks is sufficient to induce insulin resistance and NAFLD in mice.

In this work, the utilization of calcium and strontium by the (Ca2+ + Mg2+)ATPase of the basolateral plasma membrane of renal proximal convoluted tubules were compared. [90Sr]Sr2+ and [45Ca]Ca2+ uptake by vesicles derived from this membrane were strictly dependent on ATP and Mg2+, and no other nucleotide was able to support the transport. Each cation inhibited the uptake of the other one in a purely competitive fashion (the same Vmax; increased K0.5), without causing a significant change in the influx rate. These results indicate that both cations bind at the same transport site on the enzyme, facing the cytosolic surface of the cell. The K0.5 for Sr2+ obtained for (Sr2+ + Mg2+)ATPase activity was 13.1 ± 0.2 µM and for Sr2+ uptake was 13.4 ± 0.1 µM. They were higher than K0.5 for Ca2+ obtained for (Ca2+ + Mg2+)ATPase activity (0.42 ± 0.03 µM) and for Ca2+ uptake (0.28 ± 0.02 µM). It is postulated that the lower ATPase affinity for Sr2+ is associated with greater steric difficulties for the occupation by this cation of the binding and transport sites, as a consequence of its greater crystal ionic radius (1.13 Å for Sr2+ against 0.99 Å for Ca2+).

Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial–mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.

Food additives are compounds used in order to improve food palatability, texture, and shelf life. Despite a significant effort to assure safety of use, toxicological analysis of these substances, generally, rely on their direct toxicity to target organs (liver and kidney) or their genotoxic effects. Much less attention is paid to the effects of these compounds on cells of the immune system. This is of relevance given that metabolic dysregulation and obesity have a strong immune-mediated component. Obese individuals present a state of chronic low-grade inflammation that contributes to the establishment of insulin resistance and other metabolic abnormalities known as the metabolic syndrome. Obesity and metabolic syndrome are currently recognized as worldwide epidemics that pose a profound socioeconomic impact and represent a concern to public health. Cells of the immune system contribute to both the maintenance of \"lean homeostasis\" and the metabolic dysregulation observed in obese individuals. Although much attention has been drawn in the past decades to obesity and metabolic syndrome as a result of ingesting highly processed food containing large amounts of fat and simple sugars, mounting evidence suggest that food additives may also be important contributors to metabolic derangement. Herein, we review pieces of evidence from the literature showing that food additives have relevant effects on cells of the immune system that could contribute to immune-mediated metabolic dysregulation. Considering their potential to predispose individuals to develop obesity and metabolic syndrome, their use should be taken with caution or maybe revisited.

Clotrimazole is an azole derivative with promising anti-cancer effects. This drug interferes with the activity of glycolytic enzymes altering their cellular distribution and inhibiting their activities. The aim of the present study was to analyze the effects of clotrimazole on the growth pattern of breast cancer cells correlating with their metabolic profiles. Three cell lines derived from human breast tissue (MCF10A, MCF-7 and MDA-MB-231) that present increasingly aggressive profiles were used. Clotrimazole induces a dose-dependent decrease in glucose uptake in all three cell lines, with K(i) values of 114.3±11.7, 77.1±7.8 and 37.8±4.2 µM for MCF10A, MCF-7 and MDA-MB-231, respectively. Furthermore, the drug also decreases intracellular ATP content and inhibits the major glycolytic enzymes, hexokinase, phosphofructokinase-1 and pyruvate kinase, especially in the highly metastatic cell line, MDA-MB-231. In this last cell lineage, clotrimazole attenuates the robust migratory response, an effect that is progressively attenuated in MCF-7 and MCF10A, respectively. Moreover, clotrimazole reduces the viability of breast cancer cells, which is more pronounced on MDA-MB-231. Clotrimazole presents deleterious effects on two human breast cancer cell lines metabolism, growth and migration, where the most aggressive cell line is more affected by the drug. Moreover, clotrimazole presents little or no effect on a non-tumor human breast cell line. These results suggest, at least for these three cell lines studied, that the more aggressive the cell is the more effective clotrimazole is.

Arbovirus infections, including dengue, Zika, and chikungunya, constitute significant global health threats. The epidemiology of these diseases is closely tied to the biology and ecology of the mosquito , particularly regarding its vector competence-the mosquito's ability to acquire, maintain, and transmit pathogens. While genetic variations among mosquito populations have traditionally received the most attention and are often regarded as the main determinants of vector competence, life history components, including immune history, microbiota composition, and nutritional status, are increasingly recognized as critical modulators of this trait. In this context, the increasing prevalence of diet-induced obesity and diabetes in human hosts-a condition that alters blood plasma composition-may reshape the mosquito´s nutritional and immunological landscape. This study investigated the impact of these conditions on biology and Zika virus (ZIKV) infection. For this, AG129 mice were fed a high-fat, high-sucrose (HFHS) diet for 20 weeks to develop weight gain and insulin resistance. By comparing mosquitoes fed on healthy and diabetic-obese mice, we assessed changes in life history traits, immunometabolic parameters, and transcriptomic profiles. Notably, mosquitoes fed on HFHS-fed mice showed reduced survival, altered lipid profile and a significant reduction in midgut and systemic ZIKV infection levels, which correlated with distinct transcriptomic alterations in genes related to gut metabolism and homeostasis. These findings demonstrate that the host's metabolic state is a critical modulator of mosquito physiology, increasing mosquito mortality while reducing ZIKV infection levels. This highlights that host-centric factors, such as the rising prevalence of metabolic syndrome, are an overlooked variable that may have complex epidemiological consequences for arbovirus transmission by mosquitoes.

Background The high prevalence of metabolic syndrome in low- and middle-income countries is linked to an increase in Western diet consumption, characterized by a high intake of processed foods, which impacts the levels of blood sugar and lipids, hormones, and cytokines. Hematophagous insect vectors, such as the yellow fever mosquito Aedes aegypti , rely on blood meals for reproduction and development and are therefore exposed to the components of blood plasma. However, the impact of the alteration of blood composition due to malnutrition and metabolic conditions on mosquito biology remains understudied. Methods In this study, we investigated the impact of whole-blood alterations resulting from a Western-type diet on the biology of Ae. aegypti . We kept C57Bl6/J mice on a high-fat, high-sucrose (HFHS) diet for 20 weeks and followed biological parameters, including plasma insulin and lipid levels, insulin tolerance, and weight gain, to validate the development of metabolic syndrome. We further allowed Ae. aegypti mosquitoes to feed on mice and tracked how altered host blood composition modulated parameters of vector capacity. Results Our findings identified that HFHS-fed mice resulted in reduced mosquito longevity and increased fecundity upon mosquito feeding, which correlated with alteration in the gene expression profile of nutrient sensing and physiological and metabolic markers as studied up to several days after blood ingestion. Conclusions Our study provides new insights into the overall effect of alterations of blood components on mosquito biology and its implications for the transmission of infectious diseases in conditions where the frequency of Western diet-induced metabolic syndromes is becoming more frequent. These findings highlight the importance of addressing metabolic health to further understand the spread of mosquito-borne illnesses in endemic areas. Graphical Abstract

Overweight and obesity have become epidemic worldwide and are linked to sedentary lifestyle and the consumption of processed foods and drinks. Citrate is a metabolite that plays central roles in carbohydrate and lipid metabolism. In addition, citrate is the additive most commonly used by the food industry, and therefore is highly consumed. Extracellular citrate can freely enter the cells via the constitutively expressed plasma membrane citrate transporter. Within the cytosol, citrate is readily metabolised by ATP-citrate lyase into acetyl-CoA – the metabolic precursor of endogenously produced lipids and cholesterol. We therefore hypothesised that the citrate ingested from processed foods and drinks could contribute to increased postprandial fat production and weight gain. To test our hypothesis, we administered citrate to mice through their drinking water with or without sucrose and monitored their weight gain and other metabolic parameters. Our results showed that mice receiving citrate or citrate+sucrose did not show increased weight gain or an increase in the weight of the liver, skeletal muscles or adipose tissues (AT). Moreover, the plasma lipid profiles (TAG, total cholesterol, LDL and HDL) were similar across all groups. However, the group receiving citrate+sucrose showed augmented fasting glycaemia, glucose intolerance and the expression of pro-inflammatory cytokines (TNF- α , IL-1 β , IL-6 and IL-10) in their AT. Therefore, our results suggest that citrate consumption contributes to increased AT inflammation and altered glucose metabolism, which is indicative of initial insulin resistance. Thus, citrate consumption could be a previously unknown causative agent for the complications associated with obesity.

Serotonin (5-HT) is a hormone that has been implicated in the regulation of many physiological and pathological events. One of the most intriguing properties of this hormone is its ability to up-regulate mitosis. Moreover, 5-HT stimulates glucose uptake and up-regulates PFK activity through the 5-HT 2A receptor, resulting in the phosphorylation of a tyrosine residue of PFK and the intracellular redistribution of PFK within skeletal muscle. The present study investigated some of the signaling intermediates involved in the effects of 5-HT on 6-phosphofructo-1-kinase (PFK) regulation from skeletal muscle using kinetic assessments, immunoprecipitation, and western blotting assays. Our results demonstrate that 5-HT stimulates PFK from skeletal muscle via phospholipase C (PLC). The activation of PLC in skeletal muscle leads to the recruitment of protein kinase C (PKC) and calmodulin and the stimulation of calmodulin kinase II, which associates with PFK upon 5-HT action. Alternatively, 5-HT loses its ability to up-regulate PFK activity when Janus kinase is inhibited, suggesting that 5-HT is able to control glycolytic flux in the skeletal muscle of mice by recruiting different pathways and controlling PFK activity.

Although demonstrated as a selective anticancer drug, the clinical use of clotrimazole (CTZ) is limited due to its low solubility in hydrophilic fluids. Thus, we prepared a water-soluble nanomicellar formulation of CTZ (nCTZ) and tested on the human breast cancer cell line MCF-7 biology. CTZ was nanoencapsulated in tween 80 micelles, which generated nanomicelles of, approximately, 17 nm of diameter. MCF-7 cells were treated with nCTZ and unencapsulated DMSO-solubilized drug (sCTZ) was used for comparison. After treatment, the cells were evaluated in terms of metabolism, proliferation, survival and structure. We found that nCTZ was more efficient than sCTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes. Moreover, this increased activity was also observed for lactate production, intracellular ATP content, ROS production and antioxidant potential. As a consequence, nCTZ-treated MCF-7 cells displayed alterations to the plasma membrane, mitochondria and the nucleus. Finally, nCTZ induced both apoptosis and necrosis in MCF-7 cells. MCF-7 cells are more sensible to nCTZ than to sCTZ. This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism. Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine.