Dietary intake of Perfluorooctanesulfonic acid (PFOS) and glucose homeostasis parameters in a non-diabetic senior population.

BACKGROUND: Endocrine disruptors (EDs) have emerged as potential contributors to the development of type-2 diabetes. Perfluorooctane sulfonate (PFOS), is one of these EDs linked with chronic diseases and gathered attention due to its widespread in food. OBJECTIVE: To assess at baseline and after 1-year of follow-up associations between estimated dietary intake (DI) of PFOS, and glucose homeostasis parameters and body-mass-index (BMI) in a senior population of 4600 non-diabetic participants from the PREDIMED-plus study. METHODS: Multivariable linear regression models were conducted to assess associations between baseline PFOS-DI at lower bound (LB) and upper bound (UB) established by the EFSA, glucose homeostasis parameters and BMI. RESULTS: Compared to those in the lowest tertile, participants in the highest tertile of baseline PFOS-DI in LB and UB showed higher levels of HbA1c [ß-coefficient(CI)] [0.01 %(0.002 to 0.026), and [0.06 mg/dL(0.026 to 0.087), both p-trend ≤ 0.001], and fasting plasma glucose in the LB PFOS-DI [1.05 mg/dL(0.050 to 2.046),p-trend = 0.022]. Prospectively, a positive association between LB of PFOS-DI and BMI [0.06 kg/m2(0.014 to 0.106) per 1-SD increment of energy-adjusted PFOS-DI was shown. Participants in the top tertile showed an increase in HOMA-IR [0.06(0.016 to 0.097), p-trend = 0.005] compared to participants in the reference tertile after 1-year of follow-up. DISCUSSION: This is the first study to explore the association between DI of PFOS and glucose homeostasis. In this study, a high baseline DI of PFOS was associated with a higher levels of fasting plasma glucose and HbA1c and with an increase in HOMA-IR and BMI after 1-year of follow-up.

Microbial Phenolic Metabolites Are Associated with Improved Cognitive Health.

SCOPE: Diets rich in polyphenols has been associated with better cognitive performance. The aim of this study is to assess the relationship between microbial phenolic metabolites (MPM) in urine and cognition in the context of an older population at high cardiovascular risk. METHODS AND RESULTS: A cross-sectional analysis is conducted in 400 individuals of the PREDIMED-Plus study. Liquid chromatography coupled to mass spectrometry is used to identify urinary MPM. Mediterranean diet (MedDiet) adherence is estimated with a 17-item questionnaire and cognitive function is evaluated with a battery of neuropsychological tests. Multivariable-adjusted linear regression models are fitted to assess the relationship of urinary MPM with the MedDiet and cognitive tests. Protocatechuic acid and enterolactone glucuronide are associated with higher adherence to the MedDiet. Regarding cognitive function, protocatechuic acid, vanillic acid glucuronide, 3-hydroxybenzoic acid, enterodiol glucuronide, and enterolactone glucuronide are directly associated with a global composite score of all the cognitive tests. Furthermore, protocatechuic acid and enterolactone glucuronide are associated with higher scores in the Mini-Mental State Examination, whereas enterodiol glucuronide is associated with improved Clock Drawing Test scores. CONCLUSIONS: These results suggest that the MedDiet is linked to MPM associated with better cognitive performance in an older population.

Association of adiposity and its changes over time with COVID-19 risk in older adults with overweight/obesity and metabolic syndrome: a longitudinal evaluation in the PREDIMED-Plus cohort.

BACKGROUND: Cross-sectionally, older age and obesity are associated with increased coronavirus disease-2019 (COVID-19) risk. We assessed the longitudinal associations of baseline and changes in adiposity parameters with COVID-19 incidence in older adults at high cardiovascular risk. METHODS: This analysis included 6874 men and women (aged 55-75 years) with overweight/obesity and metabolic syndrome in the PREDIMED-Plus lifestyle intervention trial for cardiovascular risk reduction. Body weight, body-mass-index (BMI), waist circumference, waist-to-height ratio (WHtR), and a body shape index (ABSI) were measured at baseline and annual follow-up visits. COVID-19 was ascertained by an independent Event Committee until 31 December 2021. Cox regression models were fitted to evaluate the risk of COVID-19 incidence based on baseline adiposity parameters measured 5-6 years before the pandemic and their changes at the visit prior to censoring. RESULTS: At the time of censoring, 653 incident COVID-19 cases occurred. Higher baseline body weight, BMI, waist circumference, and WHtR were associated with increased COVID-19 risk. During the follow-up, every unit increase in body weight (HRadj (95%CI): 1.01 (1.00, 1.03)) and BMI (HRadj: 1.04 (1.003, 1.08)) was associated with increased COVID-19 risk. CONCLUSIONS: In older adults with overweight/obesity, clinically significant weight loss may protect against COVID-19. TRIAL REGISTRATION: This study is registered at the International Standard Randomized Controlled Trial (ISRCT; http://www.isrctn.com/ISRCTN89898870 ).

Dietary Iron, Anemia Markers, Cognition, and Quality of Life in Older Community-Dwelling Subjects at High Cardiovascular Risk.

Anemia causes hypo-oxygenation in the brain, which could lead to cognitive disorders. We examined dietary iron intake as well as anemia markers (i.e., hemoglobin, hematocrit, mean corpuscular volume) and diabetes coexistence in relation to neuropsychological function and quality of life. In this study, 6117 community-dwelling adults aged 55-75 years (men) and 60-75 years (women) with overweight/obesity and metabolic syndrome were involved. We performed the Mini-Mental State Examination (MMSE), the Trail Making Test parts A and B (TMT-A/B), Semantic Verbal Fluency of animals (VFT-a), Phonological Verbal Fluency of letter P (VFT-p), Digit Span Test (DST), the Clock Drawing Test (CDT), and the Short Form-36 Health Survey (SF36-HRQL test). Dietary iron intake did not influence neuropsychological function or quality of life. However, anemia and lower levels of anemia markers were associated with worse scores in all neurophysiological and SF36-HRQL tests overall, but were especially clear in the MMSE, TMT-B (cognitive flexibility), and the physical component of the SF36-HRQL test. The relationships between anemia and diminished performance in the TMT-A/B and VFT tasks were notably pronounced and statistically significant solely among participants with diabetes. In brief, anemia and reduced levels of anemia markers were linked to inferior cognitive function, worse scores in different domains of executive function, as well as a poorer physical, but not mental, component of quality of life. It was also suggested that the coexistence of diabetes in anemic patients may exacerbate this negative impact on cognition. Nevertheless, dietary iron intake showed no correlation with any of the outcomes. To make conclusive recommendations for clinical practice, our findings need to be thoroughly tested through methodologically rigorous studies that minimize the risk of reverse causality.

Two-Year Changes in Physical Activity and Concurrent Changes in Cognitive Function in a Cohort of Adults with Metabolic Syndrome.

BACKGROUND: It has been proposed that physical activity (PA) could prevent cognitive decline. OBJECTIVE: To evaluate the association between changes in PA and changes in cognitive function in a cohort of adults with metabolic syndrome. METHODS: Longitudinal observational study including 5,500 adults (mean age 65 years, SD = 5; women = 49.3% ) with metabolic syndrome. Participants underwent physical activity measurements and cognitive evaluation at baseline and at two-years of follow-up. PA was quantified using the Minnesota questionnaire-shortened version. Cognitive function was evaluated using a battery of tests: Mini-Mental Test Examination, Clock Drawing Test, Trail Making Test A and B, Verbal Fluency Test, and Digit Span. The primary outcome was two-year change in cognition, measured through the Global Composite Score (GCS) of all neuropsychological tests. Multivariable-adjusted linear regression models were fitted with baseline PA and their changes as the main exposures and changes in cognitive function as the outcome. RESULTS: No significant association was found between PA levels (or their changes) in the GCS of cognitive function. A greater increase in PA levels was associated with a more favorable two-year change in the Trail Making Test A (Q4 versus Q1: b = - 2.24s, 95% CI -4.36 to -0.12s; p-trend = 0.020). No significant association was found for other neuropsychological test. CONCLUSION: Our results do not support an association between increases in PA and the evolution of the global cognitive function at two-year in an intervention trial which included PA promotion in one of its two randomized arms, but they suggested a possible beneficial effect of PA on attentional function in older adults.

Higher versus lower nut consumption and changes in cognitive performance over two years in a population at risk of cognitive decline: a cohort study.

BACKGROUND: Tree nuts and peanuts (henceforth, nuts) are nutrient-dense foods rich in neuroprotective components; thus, their consumption could benefit cognitive health. However, evidence to date is limited and inconsistent regarding the potential benefits of nuts for cognitive function. OBJECTIVE: To prospectively evaluate the association between nut consumption and 2-y changes in cognitive performance in older adults at cognitive decline risk. METHODS: A total of 6,630 participants aged 55 to 75 y (mean age 65.0±4.9 y, 48.4% women) with overweight/obesity and metabolic syndrome completed a validated semi-quantitative food frequency questionnaire and a comprehensive battery of neuropsychological tests at baseline and a 2-y follow-up. Composite cognitive scores were used to assess global, general, attention, and executive function domains. Nut consumption was categorized as <1, ≥1 to <3, ≥3 to <7, and ≥7 servings/wk (1 serving=30 g). Multivariable-adjusted linear regression models were fitted to assess associations between baseline nut consumption and 2-y cognitive changes. RESULTS: Nut consumption was positively associated with 2-y changes in general cognitive function (P-trend <0.001). Compared with participants consuming <1 serving/wk of nuts, those categorized as consuming ≥3 to <7 and ≥7 servings/wk showed more favorable changes in general cognitive performance (ß z-score [95% CI] = 0.06 [0.00,0.12] and 0.13 [0.06,0.20], respectively). No significant changes were observed in the multivariable-adjusted models for other cognitive domains assessed. CONCLUSION: Frequent nut consumption was associated with a smaller decline in general cognitive performance over 2 y in older adults at risk of cognitive decline. Randomized clinical trials to verify our findings are warranted.

Dietary intake of polychlorinated dibenzo-p-dioxins and furans, adiposity and obesity status.

INTRODUCTION: The principal source of exposure to Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) in humans comes from food intake. PCDD/Fs, are a family of potential endocrine disruptors and have been associated with different chronic diseases such as diabetes and hypertension. However, studies assessing the relationship between dietary exposure to PCDD/Fs and adiposity or obesity status in a middle-aged population are limited. OBJECTIVE: To assess cross-sectionally and longitudinally the associations between estimated dietary intake (DI) of PCDD/Fs and body mass index (BMI), waist circumference, and the prevalence/incidence of obesity and abdominal obesity in a middle-aged population. METHODS: In 5899 participants aged 55-75 years (48% women) living with overweight/obesity from the PREDIMED-plus cohort, PCDD/Fs DI was estimated using a 143-item validated food-frequency questionnaire, and the levels of food PCDD/F expressed as Toxic Equivalents (TEQ). Consequently, cross-sectional and prospective associations between baseline PCDD/Fs DI (in pgTEQ/week) and adiposity or obesity status were assessed at baseline and after 1-year follow-up using multivariable cox, logistic or linear regression models. RESULTS: Compared to participants in the first PCDD/F DI tertile, those in the highest tertile presented a higher BMI (ß-coefficient [confidence interval]) (0.43kg/m2 [0.22; 0.64]; P-trend <0.001), a higher waist circumference (1.11 cm [0.55; 1.66]; P-trend <0.001), and a higher prevalence of obesity and abdominal obesity (1.05 [1.01; 1.09] and 1.02 [1.00; 1.03]; P-trend = 0.09 and 0.027, respectively). In the prospective analysis, participants in the top PCDD/F DI baseline tertile showed an increase in waist circumference compared with those in the first tertile after 1-year of follow-up (ß-coefficient 0.37 cm [0.06; 0.70]; P-trend = 0.015). CONCLUSION: Higher DI of PCDD/Fs was positively associated with adiposity parameters and obesity status at baseline and with changes in waist circumference after 1-year of follow-up in subjects living with overweight/obesity. Further large prospective studies using a different population with longer follow-up periods are warranted in the future to strengthen our results.

Efficacy of Different Modalities and Frequencies of Physical Exercise on Glucose Control in People with Prediabetes (GLYCEX Randomised Trial).

To assess the efficacy of different modalities and frequencies of physical exercise on glycaemic control in adults with prediabetes. A two-phase, parallel, randomised, controlled clinical trial will be carried out, in 210 participants. In phase 1, 120 participants will be randomized into four arms: (1) aerobic exercise, (2) aerobic exercise combined with resistance, (3) high-intensity intervallic exercise and (4) control group. In phase 2, 90 new participants will be randomized into three arms, using the exercise modality that showed the best glycaemic control in phase 1 in the following manner: (1) frequency of 5 days/week, (2) frequency of 3 days/week and (3) frequency of 2 days/week. The control group (n = 30) will be included in phase 1 to evaluate the effect of any type of intervention versus no intervention. Data collection will be performed at baseline and after 15 weeks of follow up. Sociodemographic data, medication, comorbidity, blood biochemical parameters, blood pressure, anthropometric measurements, body composition, physical activity, sedentary lifestyle, diet, smoking, alcohol consumption, quality of life and sleep questionnaires will be collected. Physical activity, sedentary behaviour and sleep will be further determined with an accelerometer, and continuous glycaemia will be determined with a glycaemic monitor, both during seven days, at two time points. The main dependent variable will be the reduction in the mean amplitude of glycaemic excursions. The impact of these interventions on health will also be evaluated through gene expression analysis in peripheral blood cells. The results of this study will contribute to a better understanding of the mechanisms behind the glucose response to physical exercise in a population with prediabetes as well as improve physical exercise prescriptions for diabetes prevention. Increasing glycaemic control in people with prediabetes through physical exercise offers an opportunity to prevent diabetes and reduce associated comorbidities and health costs.

Insights behind the Relationship between Colorectal Cancer and Obesity: Is Visceral Adipose Tissue the Missing Link?

Colorectal cancer (CRC) is a major health problem worldwide, with an estimated 1.9 million new cases and 915,880 deaths in 2020 alone. The etiology of CRC is complex and involves both genetic and lifestyle factors. Obesity is a major risk factor for CRC, and the mechanisms underlying this link are still unclear. However, the generalized inflammatory state of adipose tissue in obesity is thought to play a role in the association between CRC risk and development. Visceral adipose tissue (VAT) is a major source of proinflammatory cytokines and other factors that contribute to the characteristic systemic low-grade inflammation associated with obesity. VAT is also closely associated with the tumor microenvironment (TME), and recent evidence suggests that adipocytes within the TME undergo phenotypic changes that contribute to tumor progression. In this review, we aim to summarize the current evidence linking obesity and CRC, with a focus on the role of VAT in tumor etiology and progression.

Longitudinal association of dietary carbohydrate quality with visceral fat deposition and other adiposity indicators.

BACKGROUND & AIMS: The quality of dietary carbohydrates rather than total carbohydrate intake may determine the accumulation of visceral fat; however, to date, few studies have examined the impact of diet on adiposity using specific imaging techniques. Thus, the aim of this prospective study was to investigate the association between concurrent changes in carbohydrate quality index (CQI) and objectively-quantified adiposity distribution over a year. METHODS: We analyzed a cohort of 1476 participants aged 55-75 years with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus randomized controlled trial. Dietary intake information was obtained at baseline, 6- and 12-months from a validated 143-item semi-quantitative food-frequency questionnaire, and CQI (range: 4 to 20) was calculated based on four dietary criteria: total dietary fibre, glycemic index, wholegrain/total grain carbohydrate ratio, and solid/total carbohydrate ratio. Overall and regional adiposity (total body fat, visceral fat and android-to-gynoid fat ratio) was quantified using dual-energy X-ray absorptiometry at all three time points. Multiple adjusted linear mixed-effects models were used to assess associations between concurrent changes in repeatedly measured CQI and adiposity over time. RESULTS: After controlling for potential confounding factors, a 3-point increment in CQI over 12-month follow-up was associated with a decrease in visceral fat (ß -0.067 z-score, 95% CI -0.088; -0.046, p < 0.001), android-to-gynoid fat ratio (-0.038, -0.059; -0.017, p < 0.001), and total fat (-0.064, -0.080; -0.047, p < 0.001). Fibre intake and the ratio of wholegrain/total grain showed the strongest inverse associations with all adiposity indicators. CONCLUSIONS: In this prospective cohort of older adults with overweight/obesity and MetS, we found that improvements in dietary carbohydrate quality over a year were associated with concurrent favorable changes in visceral and overall fat deposition. These associations were mostly driven by dietary fibre and the wholegrain/total grain ratio. TRIAL REGISTRATION: The trial was registered at the International Standard Randomized. CONTROLLED TRIAL: (ISRCTN: http://www.isrctn.com/ISRCTN89898870) with number 89898870 and registration date of 24 July 2014, retrospectively registered.

Morbid liver manifestations are intrinsically bound to metabolic syndrome and nutrient intake based on a machine-learning cluster analysis.

Metabolic syndrome (MetS) is one of the most important medical problems around the world. Identification of patient´s singular characteristic could help to reduce the clinical impact and facilitate individualized management. This study aimed to categorize MetS patients using phenotypical and clinical variables habitually collected during health check-ups of individuals considered to have high cardiovascular risk. The selected markers to categorize MetS participants included anthropometric variables as well as clinical data, biochemical parameters and prescribed pharmacological treatment. An exploratory factor analysis was carried out with a subsequent hierarchical cluster analysis using the z-scores from factor analysis. The first step identified three different factors. The first was determined by hypercholesterolemia and associated treatments, the second factor exhibited glycemic disorders and accompanying treatments and the third factor was characterized by hepatic enzymes. Subsequently four clusters of patients were identified, where cluster 1 was characterized by glucose disorders and treatments, cluster 2 presented mild MetS, cluster 3 presented exacerbated levels of hepatic enzymes and cluster 4 highlighted cholesterol and its associated treatments Interestingly, the liver status related cluster was characterized by higher protein consumption and cluster 4 with low polyunsaturated fatty acid intake. This research emphasized the potential clinical relevance of hepatic impairments in addition to MetS traditional characterization for precision and personalized management of MetS patients.

One-year longitudinal association between changes in dietary choline or betaine intake and cardiometabolic variables in the PREvención con DIeta MEDiterránea-Plus (PREDIMED-Plus) trial.

BACKGROUND: Choline and betaine intakes have been related to cardiovascular health. OBJECTIVES: We aimed to explore the relation between 1-y changes in dietary intake of choline or betaine and 1-y changes in cardiometabolic and renal function traits within the frame of the PREDIMED (PREvención con DIeta MEDiterránea)-Plus trial. METHODS: We used baseline and 1-y follow-up data from 5613 participants (48.2% female and 51.8% male; mean ± SD age: 65.01 ± 4.91 y) to assess cardiometabolic traits, and 3367 participants to assess renal function, of the Spanish PREDIMED-Plus trial. Participants met ≥3 criteria of metabolic syndrome and had overweight or obesity [BMI (in kg/m2) ≥27 and ≤40]. These criteria were similar to those of the PREDIMED parent study. Dietary intakes of choline and betaine were estimated from the FFQ. RESULTS: The greatest 1-y increase in dietary choline or betaine intake (quartile 4) was associated with improved serum glucose concentrations (-3.39 and -2.72 mg/dL for choline and betaine, respectively) and HbA1c levels (-0.10% for quartile 4 of either choline or betaine intake increase). Other significant changes associated with the greatest increase in choline or betaine intake were reduced body weight (-2.93 and -2.78 kg, respectively), BMI (-1.05 and -0.99, respectively), waist circumference (-3.37 and -3.26 cm, respectively), total cholesterol (-4.74 and -4.52 mg/dL, respectively), and LDL cholesterol (-4.30 and -4.16 mg/dL, respectively). Urine creatinine was reduced in quartile 4 of 1-y increase in choline or betaine intake (-5.42 and -5.74 mg/dL, respectively). CONCLUSIONS: Increases in dietary choline or betaine intakes were longitudinally related to improvements in cardiometabolic parameters. Markers of renal function were also slightly improved, and they require further investigation.This trial was registered at https://www.isrctn.com/ as ISRCTN89898870.

Dairy Product Consumption and Changes in Cognitive Performance: Two-Year Analysis of the PREDIMED-Plus Cohort.

SCOPE: Dairy consumption has been suggested to impact cognition; however, evidence is limited and inconsistent. This study aims to longitudinally assess the association between dairy consumption with cognitive changes in an older Spanish population at high cardiovascular disease risk. METHODS AND RESULTS: Four thousand six hundred sixty eight participants aged 55-75 years, completed a validated food frequency questionnaire at baseline and a neuropsychological battery of tests at baseline and 2-year follow-up. Multivariable linear regression models are used, scaled by 100 (i.e., the units of ß correspond to 1 SD/100), to assess associations between baseline tertile daily consumption and 2-year changes in cognitive performance. Participants in the highest tertile of total milk and whole-fat milk consumption have a greater decline in global cognitive function (ß: -4.71, 95% CI: -8.74 to -0.69, p-trend = 0.020 and ß: -6.64, 95% CI: -10.81 to -2.47, p-trend = 0.002, respectively) compared to those in the lowest tertile. No associations are observed between low fat milk, yogurt, cheese or fermented dairy consumption, and changes in cognitive performance. CONCLUSION: Results suggest there are no clear prospective associations between consumption of most commonly consumed dairy products and cognition, although there may be an association with a greater rate of cognitive decline over a 2-year period in older adults at high cardiovascular disease risk for whole-fat milk.

Plaque-targeted, proteolysis-resistant, activatable and MRI-visible nano-GLP-1 receptor agonist targets smooth muscle cell differentiation in atherosclerosis.

Background: Glucagon-like peptide-1 receptor (GLP-1R) agonists are powerful glycemia-lowering agents, which have systematically been shown to lower cardiovascular events and mortality. These beneficial effects were difficult to pinpoint within atherosclerotic plaque due to lack of particular specificity of such agonists to the vascular cells and an inadequate understanding of the GLP-1R expression in atherosclerosis. Here, we hypothesized that the direct engagement of the GLP-1R in atherosclerosis by targeted agonists will alleviate vascular inflammation and plaque burden, even at a very low dose. Methods: The expression of GLP-1 receptor (GLP-1R, Glp1r mRNA) in human lesions with pathologic intimal thickening, Apoe-/- mouse atheroma and cultured immune/non-immune cells was investigated using genetic lineage tracing, Southern blotting and validated antisera against human GLP-1R. Protease-resistant and "activatable" nanoparticles (NPs) carrying GLP-1R agonist liraglutide (GlpNP) were engineered and synthesized. Inclusion of gadolinium chelates into GlpNP allowed for imaging by MRI. Atherosclerotic Apoe-/- mice were treated intravenously with a single dose (30 µg/kg of liraglutide) or chronically (1 µg/kg, 6 weeks, 2x/week) with GlpNP, liraglutide or control NPs, followed by assessment of metabolic parameters, atheroma burden, inflammation and vascular function. Results: Humal plaque specimens expressed high levels of GLP-1R within the locus of de-differentiated smooth muscle cells that also expressed myeloid marker CD68. However, innate immune cells under a variety of conditions expressed very low levels of Glp1r, as seen in lineage tracing and Southern blotting experiments examining full-length open reading frame mRNA transcripts. Importantly, de-differentiated vascular smooth muscle cells demonstrated significant Glp1r expression levels, suggesting that these could represent the cells with predominant Glp1r-positivity in atherosclerosis. GlpNP resisted proteolysis and demonstrated biological activity including in vivo glycemia lowering at 30 µg/kg and in vitro cholesterol efflux. Activatable properties of GlpNP were confirmed in vitro by imaging cytometry and in vivo using whole organ imaging. GlpNP targeted CD11b+/CD11c+ cells in circulation and smooth muscle cells in aortic plaque in Apoe-/- mice when assessed by MRI and fluorescence imaging. At a very low dose of 1 µg/kg, previously known to have little effect on glycemia and weight loss, GlpNP delivered i.v. for six weeks reduced triglyceride-rich lipoproteins in plasma, plaque burden and plaque cholesterol without significant effects on weight, glycemia and plasma cholesterol levels. Conclusions: GlpNP improves atherosclerosis at weight-neutral doses as low as 1 µg/kg with the effects independent from the pancreas or the central nervous system. Our study underlines the importance of direct actions of GLP-1 analogs on atherosclerosis, involving cholesterol efflux and inflammation. Our findings are the first to suggest the therapeutic modulation of vascular targets by GlpNP, especially in the context of smooth muscle cell inflammation.

Publisher Correction: Systemically-delivered biodegradable PLGA alters gut microbiota and induces transcriptomic reprogramming in the liver in an obesity mouse model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Insights into the Role of Bioactive Food Ingredients and the Microbiome in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease mainly associated with aging and, to date, its causes are still largely unknown. It has been shown that dietary habits can accelerate or delay the occurrence of aging-related diseases; however, their potential role in IPF development has been underestimated so far. The present review summarizes the evidence regarding the relationship between diet and IPF in humans, and in animal models of pulmonary fibrosis, in which we discuss the bioactivity of specific dietary food ingredients, including fatty acids, peptides, amino acids, carbohydrates, vitamins, minerals and phytochemicals. Interestingly, many animal studies reveal preventive and therapeutic effects of particular compounds. Furthermore, it has been recently suggested that the lung and gut microbiota could be involved in IPF, a relationship which may be linked to changes in immunological and inflammatory factors. Thus, all the evidence so far puts forward the idea that the gut-lung axis could be modulated by dietary factors, which in turn have an influence on IPF development. Overall, the data reviewed here support the notion of identifying food ingredients with potential benefits in IPF, with the ultimate aim of designing nutritional approaches as an adjuvant therapeutic strategy.

Systemically-delivered biodegradable PLGA alters gut microbiota and induces transcriptomic reprogramming in the liver in an obesity mouse model.

Biodegradable materials, including the widely used poly (lactic-co-glycolic acid) (PLGA) nanoparticles contained in slow-release drug formulations, scaffolds and implants, are ubiquitous in modern biomedicine and are considered inert or capable of being metabolized through intermediates such as lactate. However, in the presence of metabolic stress, such as in obesity, the resulting degradation products may play a detrimental role, which is still not well understood. We evaluated the effect of intravenously-administered PLGA nanoparticles on the gut-liver axis under conditions of caloric excess in C57BL/6 mice. Our results show that PLGA nanoparticles accumulate and cause gut acidification in the cecum, accompanied by significant changes in the microbiome, with a marked decrease of Firmicutes and Bacteroidetes. This was associated with transcriptomic reprogramming in the liver, with a downregulation of mitochondrial function, and an increase in key enzymatic, inflammation and cell activation pathways. No changes were observed in systemic inflammation. Metagenome analysis coupled with publicly available microarray data suggested a mechanism of impaired PLGA degradation and intestinal acidification confirming an important enterohepatic axis of metabolite-microbiome interaction resulting in maintenance of metabolic homeostasis. Thus, our results have important implications for the investigation of PLGA use in metabolically-compromised clinical and experimental settings.

Nano-Antagonist Alleviates Inflammation and Allows for MRI of Atherosclerosis.

Specific targeting of inflammation remains a challenge in many pathologies, because of the necessary balance between host tolerance and efficacious inflammation resolution. Here, we discovered a short, 4-mer peptide which possesses antagonist properties towards CC chemokine receptor 2 (CCR2), but only when displayed on the surface of lipid nanoparticles. According to BLAST analysis, this peptide motif is a common repeating fragment in a number of proteins of the CC chemokine family, which are key players in the inflammatory response. In this study, self-assembled, peptide-conjugated nanoparticles (CCTV) exhibited typical properties of CCR2 antagonism, including affinity to the CCR2 receptor, inhibition of chemotactic migration of primary monocytes, and prevention from CC chemokine ligand 2 (CCL2)-induced actin polymerization. Furthermore, CCTV ameliorated NFkB activation and downregulated the secondary, but not the primary, inflammatory response in cultured macrophages. When conjugated with gadolinium or europium cryptates, CCTV enabled targeted imaging (via magnetic resonance imaging and time-resolved fluorescence) of atherosclerosis, a chronic inflammatory condition in which the CCL2/CCR2 axis is highly dysfunctional. CCTV targeted CCR2hiLy6Chi inflammatory monocytes in blood and the atherosclerotic plaque, resulting in cell-specific transcriptional downregulation of key inflammatory genes. Finally, CCTV generated pronounced inflammasome inactivation, likely mediated through reactive oxygen species scavenging and downregulation of NLRP3. In summary, our work demonstrates for the first time that a short peptide fragment presented on a nanoparticle surface exhibit potent receptor-targeted antagonist effects, which are not seen with the peptide alone. Unlike commonly used cargo-carrying, vector-directed drug delivery vehicles, CCTV nanoparticles may act as therapeutics/theranostics themselves, particularly in inflammatory conditions with CCL2/CCR2 pathogenesis, including cardiovascular disease and cancer.

Oral Phenelzine Treatment Mitigates Metabolic Disturbances in Mice Fed a High-Fat Diet.

Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT: Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.

Resveratrol Anti-Obesity Effects: Rapid Inhibition of Adipocyte Glucose Utilization.

Studies in animal models of diabetes and obesity have shown that resveratrol mitigates complications of metabolic diseases, beyond those resulting from oxidative stress. Furthermore, results obtained with cultured preadipocytes have also revealed that prolonged resveratrol treatment impairs adipogenesis. Considering the role of adipocytes in the hypertrophy of fat stores, and keeping in mind that insulin is the main trigger of excessive energy storage during post-prandial periods, the present study aimed to investigate how short-term effects of resveratrol can limit glucose disposal in a gut-adipose tissue axis. We found that resveratrol exhibits a more potent inhibitory capacity towards α-glucosidase than pancreatic lipase activity. Resveratrol also rapidly blunts glucose transport in mature fat cells by counteracting the effect of insulin and insulin-like lipogenic agents. Within two hours, resveratrol also inhibited the incorporation of glucose into lipids of adipocytes, which was unaffected by membrane cholesterol depletion. Moreover, the comparison between adipocytes with invalidated semicarbazide-sensitive amine oxidase activity and their control, or between resveratrol and several inhibitors, did not indicate that the recently described interaction of resveratrol with amine oxidases was involved in its antilipogenic effect. Caffeine and piceatannol, previously said to interact with glucose carriers, also inhibit lipogenesis in adipocytes, whereas other antioxidant phytochemicals do not reproduce such an antilipogenic effect. This study highlights the diverse first steps by which resveratrol impairs excessive fat accumulation, indicating that this natural molecule and its derivatives deserve further studies to develop their potential anti-obesity properties.