Extracellular vesicles (EVs) are emerging as novel theranostic tools. Limitations related to clinical uses are leading to a new research area on design and manufacture of artificial EVs. Several ...strategies have been reported in order to produce artificial EVs, but there has not yet been a clear criterion by which to differentiate these novel biomaterials. In this paper, we suggest for the first time a systematic classification of the terms used to build up the artificial EV landscape, based on the preparation method. This could be useful to guide the derivation to clinical trial routes and to clarify the literature. According to our classification, we have reviewed the main strategies reported to date for their preparation, including key points such as: cargo loading, surface targeting strategies, purification steps, generation of membrane fragments for the construction of biomimetic materials, preparation of synthetic membranes inspired in EV composition and subsequent surface decoration.
Scope
Perinatal maternal obesity and excessive fructose consumption have been associated with liver metabolic diseases. The study investigates whether moderate maternal high‐fat diet affects the ...liver mitochondria responses to fructose intake in adult offspring.
Methods and Results
Wistar female rats have received a standard diet (mSTD) or high‐fat diet (mHFD) (9% and 28.6% fat, respectively), before mating until the end of lactation. Male offspring were fed standard diet from weaning to adulthood and received water or fructose‐drinking water (15%) from 120 to 150 days old. Fructose induces liver mitochondrial ultrastructural alterations with higher intensity in mHFD offspring, accompanied by reduced autophagy markers. Isolated mitochondria respirometry shows unaltered ATP‐coupled oxygen consumption with increased Atp5f1b mRNA only in mHFD offspring. Fructose increases basal respiration and encoding complex I‐III mRNA, only in mSTD offspring. Uncoupled respiration is lower in mHFD mitochondria that are unable to exhibit fructose‐induced increase Ucp2 mRNA. Fructose decreases antioxidative defense markers, increases unfolded protein response and insulin resistance only in mHFD offspring without fructose‐induced hepatic lipid accumulation.
Conclusion
Mitochondrial dysfunction and homeostatic disturbances in response to fructose are early events evidencing the higher risk of fructose damage in the liver of adult offspring from dams fed an isocaloric moderate high‐fat diet.
Perinatal maternal ingestion of an isocaloric and moderate high‐fat diet (mHFD) promotes hepatic mitochondrial and metabolic alterations in adult male offspring. The offspring maladaptation causes unique responses to fructose chronic ingestion, such as insulin resistance, unfolded protein response (UPR) pathway activation, and intensification of the fructose‐induced mitochondria damage accompanied by inability to increase the respiratory chain mitochondrial genes expression.
Scope
Perinatal maternal moderately high‐fat diet (mHFD) is associated with obesity and fatty liver disease in offspring, and maternal fish oil (FO: n‐3 PUFA source) supplementation may attenuate ...these disorders. This study evaluates the effects of FO given to pregnant rats fed a mHFD on the offspring's liver at weaning.
Methods and results
Female Wistar rats receive an isoenergetic, control (CT: 10.9% from fat) or high‐fat (HF: 28.7% from fat) diet before mating, and throughout pregnancy and lactation. FO supplementation (HFFO: 2.9% of FO in the HF diet) is given to one subgroup of HF dams during pregnancy. At weaning, male and female mHFD offspring display higher body mass, adiposity, and hepatic cellular damage, steatosis, and inflammation, accompanied by increased damaged mitochondria. FO does not protect pups from systemic metabolic alterations and partially mitigates hepatic histological damage induced by mHFD only in females. However, FO reduces mRNA expression of lipogenic genes, and mitochondrial damage, and modified mitochondrial morphology suggestive of early adaptations via mitochondrial dynamics.
Conclusions
Gestational FO supplementation has limited beneficial effects on the damage caused by perinatal mHFD consumption in offspring's liver at weaning. However, FO imprinting effect on lipid metabolism and mitochondria may have beneficial long‐term outcomes.
Maternal fish oil gestational supplementation to rats fed a high‐fat diet from pre‐gestation throughout lactation didn't prevent offspring's obesogenic profile at weaning. Fish oil partially mitigated liver histopathological damage in females, but not in males. However, it reduces lipogenic genes expression and mitochondrial damage in both sexes, and induces adaptive changes in mitochondria morphology and dynamics markers with sex differences.
Scope
Non‐alcoholic fatty liver disease (NAFLD) among adolescents has been related to fructose intake. Additionally, maternal high‐fat diet (mHFD) increases the offspring susceptibility to NAFLD at ...adulthood. Here, it is hypothesized that mHFD may exacerbate the fructose impact in adolescent male rat offspring, by changing the response of contributing mechanisms to liver injury.
Methods and results
Female Wistar rats receive standard (mSTD: 9% fat) or high‐fat diet (mHFD: 29% fat) prior mating throughout pregnancy and lactation. After weaning, offspring receive standard chow and, from the 25th to 45th day, receive water or fructose–drinking water (15%). At 46 days old, fructose groups show increased adiposity, increased serum and hepatic triglycerides, regardless of maternal diet. Fructose aggravates the hepatic imbalance of redox state already exhibited by mHFD offspring. The hepatic activation of cellular repair pathways by fructose, such as unfolded protein response and macroautophagy, is disrupted only in mHFD offspring. Fructose does not change the liver morphology of mSTD offspring. However, it intensifies the liver injury already present in mHFD offspring.
Conclusion
Fructose intake during adolescence accelerates the emergence of NAFLD observed previously at the adult life of mHFD offspring, and reveals a differentiated hepatic response to metabolic insult, depending on the maternal diet.
In maternal standard diet (mSTD) adolescent offspring, fructose stress activates repair pathways, maintaining the redox balance and protecting the liver from injury. In maternal high‐fat diet (mHFD) offspring, the liver has oxidative stress (OS) and fructose stress leads to disruption on activation of hepatic repair pathways, impairing redox balance and favoring liver injury and development of non‐alcoholic fatty liver disease (NAFLD).
Perinatal maternal high-fat (HF) diet programmes offspring obesity. Obesity is associated with overactivation of the endocannabinoid system (ECS) in adult subjects, but the role of the ECS in the ...developmental origins of obesity is mostly unknown. The ECS consists of endocannabinoids, cannabinoid receptors (cannabinoid type-1 receptor (CB1) and cannabinoid type-2 receptor (CB2)) and metabolising enzymes. We hypothesised that perinatal maternal HF diet would alter the ECS in a sex-dependent manner in white and brown adipose tissue of rat offspring at weaning in parallel to obesity development. Female rats received standard diet (9 % energy content from fat) or HF diet (29 % energy content from fat) before mating, during pregnancy and lactation. At weaning, male and female offspring were killed for tissue harvest. Maternal HF diet induced early obesity, white adipocyte hypertrophy and increased lipid accumulation in brown adipose tissue associated with sex-specific changes of the ECS's components in weanling rats. In male pups, maternal HF diet decreased CB1 and CB2 protein in subcutaneous adipose tissue. In female pups, maternal HF diet increased visceral and decreased subcutaneous CB1. In brown adipose tissue, maternal HF diet increased CB1 regardless of pup sex. In addition, maternal HF diet differentially changed oestrogen receptor across the adipose depots in male and female pups. The ECS and oestrogen signalling play an important role in lipogenesis, adipogenesis and thermogenesis, and we observed early changes in their targets in adipose depots of the offspring. The present findings provide insights into the involvement of the ECS in the developmental origins of metabolic disease induced by inadequate maternal nutrition in early life.
This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD).
In Wistar rats, NAFLD model was induced by 20 weeks of ...high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs.
Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver.
The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.
Background: Using quadruple clarithromycin‐containing regimens for Helicobacter pylori eradication is controversial with high rates of macrolide resistance.
Aim: To evaluate antibiotic resistance ...rates and the efficacy of empirical and tailored nonbismuth quadruple (concomitant) therapy in a setting with cure rates <80% for triple and sequential therapies.
Methods: 209 consecutive naive H. pylori‐positive patients without susceptibility testing were empirically treated with 10‐day concomitant therapy (proton pump inhibitors (PPI), amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg; all drugs b.i.d.). Simultaneously, 89 patients with positive H. pylori culture were randomized to receive triple versus concomitant therapy for clarithromycin‐susceptible H. pylori, and sequential versus concomitant therapy for clarithromycin‐resistant strains. Eradication was confirmed with 13C‐urea breath test or histology 8 weeks after completion of treatment.
Results: Per‐protocol (PP) and intention‐to‐treat eradication rates after empirical concomitant therapy without susceptibility testing were 89% (95%CI:84–93%) and 87% (83–92%). Antibiotic resistance rates were: clarithromycin, 20%; metronidazole, 34%; and both clarithromycin and metronidazole, 10%. Regarding clarithromycin‐susceptible H. pylori, concomitant therapy was significantly better than triple therapy by per protocol 92% (82–100%) vs 74% (58–91%), p = 0.05 and by intention to treat 92% (82–100%) vs 70% (57–90%), p = 0.02. As for antibiotic‐resistant strains, eradication rates for concomitant and sequential therapies were 100% (5/5) vs 75% (3/4), for clarithromycin‐resistant/metronidazole‐susceptible strains and 75% (3/4) vs 60% (3/5) for dual‐resistant strains.
Conclusions: Empirical 10‐day concomitant therapy achieves good eradication rates, close to 90%, in settings with multiresistant H. pylori strains. Tailored concomitant therapy is significantly superior to triple therapy for clarithromycin‐susceptible H. pylori and at least as effective as sequential therapy for resistant strains.
Scope
Maternal high‐fat diet (HFD) promotes obesity and metabolic disturbances in offspring at weaning and adult life. We investigated metabolic consequences of maternal HFD in adolescent rat ...offspring and the potential benefic effects of fish oil (FO) (n‐3 polyunsaturated fatty acid source).
Methods and results
Female rats received isocaloric, standard diet (STD: 9% fat) or HFD (28.6%) before mating, and throughout pregnancy and lactation. After weaning, male offspring received standard diet and, from 25th to 45th day, received oral administration of soybean oil (SO) or FO. HFD offspring showed higher body weight and adiposity, which was not attenuated by FO. In STD offspring, FO reduced serum triglyceride and cholesterol, as expected, but not in HFD offspring. Liver of HFD offspring groups showed increased free cholesterol and FO‐treated HFD group showed lower expression of Abcg8, suggesting decreased cholesterol biliary excretion. HFD offspring presented higher hepatic expression of lipogenic markers, Srebf1 mRNA and acetyl CoA carboxylase (ACC). Serum n‐3 PUFA were decreased in FO‐treated HFD compared to FO‐treated STD offspring, which may explain the reduced hypolipidemic FO effect.
Conclusion
Maternal HFD impaired the ability of FO to reduce adiposity and serum lipids in adolescent offspring, suggesting a potential predisposition to future development of metabolic disorders
In adolescent offspring from maternal standard diet, fish oil (FO) increases serum docosahexanoic acid and eicosapentanoic acid and modulates key mechanisms of hepatic lipid metabolism, reducing serum and hepatic cholesterol and triglyceride content. In adolescent offspring from maternal high‐fat diet (HFD), the low serum n‐3 PUFA concentration and hepatic molecular changes, as ABCG8, SREBP‐1, and acetyl CoA carboxylase (ACC) expression, may disturb the FO effect, contributing to the resistance to a hypolipidemic FO effect.
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