Recent studies have demonstrated the existence of a discrete pool of cholesterol in the plasma membranes (PM) of mammalian cells-referred to as the accessible cholesterol pool-that can be detected by ...the binding of modified versions of bacterial cytolysins (e.g., anthrolysin O). When the amount of accessible cholesterol in the PM exceeds a threshold level, the excess cholesterol moves to the endoplasmic reticulum (ER), where it regulates the SREBP2 pathway and undergoes esterification. We reported previously that the Aster/Gramd1 family of sterol transporters mediates nonvesicular movement of cholesterol from the PM to the ER in multiple mammalian cell types. Here, we investigated the PM pool of accessible cholesterol in cholesterol-loaded fibroblasts with a knockdown of Aster-A and in mouse macrophages from Aster-B and Aster-A/B-deficient mice. Nanoscale secondary ion mass spectrometry (NanoSIMS) analyses revealed expansion of the accessible cholesterol pool in cells lacking Aster expression. The increased accessible cholesterol pool in the PM was accompanied by reduced cholesterol movement to the ER, evidenced by increased expression of SREBP2-regulated genes. Cosedimentation experiments with liposomes revealed that the Aster-B GRAM domain binds to membranes in a cholesterol concentration-dependent manner and that the binding is facilitated by the presence of phosphatidylserine. These studies revealed that the Aster-mediated nonvesicular cholesterol transport pathway controls levels of accessible cholesterol in the PM, as well as the activity of the SREBP pathway.
Great interest has been raised by the possible protective role of vitamin D in coronavirus disease 2019 (COVID-19), but objective data on 25(OH)vitamin D deficiency in hospitalized COVID-19 patients ...are not conclusive.
The aim of this study was to determine the prevalence of 25(OH)vitamin D deficiency in COVID-19 patients admitted to an Italian referral hospital and explore its association with clinical outcomes and the markers of disease severity.
In this single-center cohort study, 129 consecutive adult COVID-19 patients hospitalized in an Italian referral center were enrolled from March to April 2020. 25(OH)Vitamin D serum levels were assessed 48 h since hospital admission and categorized into: normal (≥30 ng/mL), insufficient (<30 - ≥20 ng/mL), moderately deficient (<20 - ≥10 ng/mL), severely deficient (<10 ng/mL).
The prevalence of 25(OH)vitamin D insufficiency, moderate deficiency and severe deficiency was 13.2%, 22.5% and 54.3%, respectively.
25(OH)Vitamin D deficiency (<20 ng/mL) was not associated with COVID-19 clinical features and outcomes. Unexpectedly, after adjusting for major confounders, a significant positive association between increasing 25(OH)vitamin D levels and in-hospital mortality (on a continuous logarithmic scale, odds ratio = 1.73 95% CI, 1.11 to 2.69; P = .016) was observed.
Very low 25(OH)vitamin D levels were highly prevalent and suggestive of deficiency among our hospitalized severe COVID-19 patients, but low 25(OH)vitamin D levels were not associated with outcome variables. Whether 25(OH)vitamin D adequacy may influence clinical outcomes in COVID-19 and the unexpected correlation between higher 25(OH)vitamin D levels and mortality require further investigations by large intervention trials.
Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are ...often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I-specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption. Treatment of obese diabetic mice with a class I- but not a class II-selective HDAC inhibitor enhanced oxidative metabolism in skeletal muscle and adipose tissue and promoted energy expenditure, thus reducing body weight and glucose and insulin levels. These effects can be ascribed to increased Pgc-1α action in skeletal muscle and enhanced PPARγ/PGC-1α signaling in adipose tissue. In vivo ChIP experiments indicated that inhibition of HDAC3 may account for the beneficial effect of the class I-selective HDAC inhibitor. These results suggest that class I HDAC inhibitors may provide a pharmacologic approach to treating type 2 diabetes.
White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to ...regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
In recent years, whey proteins (WP) have attracted increasing attention in health and disease for their bioactive functions. The aim of this study was to evaluate the benefit of WP isolate (WPI) ...supplementation in addition to nutritional counseling in malnourished advanced cancer patients undergoing chemotherapy (CT). In a single‐center, randomized, pragmatic, and parallel‐group controlled trial (ClinicalTrials.gov: NCT02065726), 166 malnourished advanced cancer patients with mixed tumor entities candidate to or undergoing CT were randomly assigned to receive nutritional counseling with (N = 82) or without (N = 84) WPI supplementation (20 g/d) for 3 months. The primary endpoint was the change in phase angle (PhA). Secondary endpoints included changes in standardized PhA (SPA), fat‐free mass index (FFMI), body weight, muscle strength, and CT toxicity (CTCAE 4.0 events). In patients with the primary endpoint assessed (modified intention‐to‐treat population), counseling plus WPI (N = 66) resulted in improved PhA compared to nutritional counseling alone (N = 69): mean difference, 0.48° (95% CI, 0.05 to 0.90) (P = .027). WPI supplementation also resulted in improved SPA (P = .021), FFMI (P = .041), body weight (P = .023), muscle strength (P < .001), and in a reduced risk of CT toxicity (risk difference, −9.8% 95% CI, −16.9 to −2.6; P = .009), particularly of severe (grade ≥ 3) events (risk difference, −30.4% 95% CI, −44.4 to −16.5; P = .001). In malnourished advanced cancer patients undergoing CT, receiving nutritional counseling, a 3‐month supplementation with WPI resulted in improved body composition, muscle strength, body weight, and reduced CT toxicity. Further trials, aimed at verifying the efficacy of this nutritional intervention on mid‐ and long‐term primary clinical endpoints in newly diagnosed specific cancer types, are warranted.
Whey proteins (WP) have attracted increasing attention in health and disease for their bioactive functions. In malnourished advanced cancer patients undergoing chemotherapy (CT) and receiving nutritional counseling, a 3‐month supplementation with WP resulted in improved body composition, muscle strength, and reduced CT toxicity.
Nutritional support, including nutritional counseling and oral nutritional supplements (ONS), has been recommended as a first-line strategy in patients with non-small cell lung cancer (NSCLC). ...Evidence on the efficacy of immunonutrition during immunotherapy in these patients is positive, but still limited some secondary endpoints, such as treatment toxicity and tolerance. We hypothesize that early systematic provision of ONS with a high-protein-high calorie mixture containing immunonutrients (Impact®) in addition to nutritional counseling, compared to nutritional counseling alone, is beneficial to patients with NSCLC receiving immunotherapy with or without chemotherapy. We designed the present study to evaluate the efficacy of early systematic provision of ONS enriched with immunonutrients compared to nutritional counseling alone, in patients with NSCLC undergoing immunotherapy. Study endpoints were: treatment response (primary endpoint: progression-free survival), treatment tolerance and toxicity, body weight, body composition, protein-calorie intake, quality of life, fatigue, muscle strength and immunological profile.
This is a pragmatic, multicentre, randomized (1:1), parallel-group, open label, controlled, pilot clinical trial (N = 180).
The improvement of efficacy of nutritional support in oncology still deserves many efforts. Immunonutrition represents a promising approach also in patients with NSCLC, but evidence on its efficacy on clinical outcomes during immunotherapy is still inconclusive. The present pilot study, which guarantees early high-quality nutritional care (assessment and treatment) to all patients in agreement with current guidelines and recommendations, could represent one of the first proofs of efficacy of early oral immunonutrition in patients with cancer undergoing immunotherapy. Further large randomized trials addressing the improvement of supportive care could be hypothesized, accordingly.
This study is registered on ClinicalTrials.gov Identifier: NCT05384873.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Malnutrition is a frequent problem in oncology and is associated with reduced response to cancer treatments, increased drug-related toxicity, higher rates of clinical complications, ...reduced quality of life (QoL) and worse prognosis. Guidelines on clinical nutrition in oncology emphasise the usefulness of early assessment of nutritional status for a prompt identification of malnutrition and the implementation of effective interventions, but no real-world clinical data are available on the adequate management of nutritional support in patients with cancer in Italy.
Methods and analysis
This is an observational, longitudinal, multicentre registry of patients with a new diagnosis of cancer or metastatic disease, candidates for active treatment. They will be identified in at least 15 Italian oncological centres, members of the Alliance Against Cancer Working Group ‘Survivorship Care and Nutritional Support’. At least 1500 patients with cancer are expected to be enrolled each year. Detailed clinical and nutritional data will be collected by oncologists and clinical nutritionists during the visits foreseen in the clinical practice, through an ad hoc developed digital platform (e-Nutracare). The effects of malnutrition and nutritional support—at diagnosis and during follow-up—on overall survival and progression-free survival, as well as on patients’ symptoms and QoL, will be investigated.
Ethics and dissemination
The study protocol was approved by the Ethics Committee of the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and from the Ethics Committees of all other participating centres. An informed consent will be obtained from each patient enrolled in the study. Study findings will be disseminated through peer-reviewed journals, conferences and patients with cancer or professional associations. The registry will allow a better monitoring of the nutritional status of patients with cancer, promoting adequate and sustainable nutritional support, with the ultimate goal of improving the care and prognosis of these patients.
The aim of this study was to evaluate the effects of mannan oligosaccharides (MOS) on gut health and performance in post-weaning piglets. In total, 40 piglets were divided into two experimental ...groups and fed a basal diet with (TRT) or without (CON) 0.2% mannan oligosaccharides for 35 days. Growth performance was determined weekly and faecal microbial composition on days 0, 14 and 35. On day 36, histometrical evaluations were performed on duodenal, jejunal, ileal, and colon samples. mRNA gene expression of inflammation-related genes was evaluated in samples of ileal Peyer’s patches (IPP). MOS administration improved feed efficiency in the last two weeks of the trial (p < 0.05), and a decreased clostridia content was found in faeces at day 14 (p = 0.05). TRT piglets showed increased duodenal villi height (p < 0.05), and reduced mRNA levels of Tumour Necrosis Factor α (p < 0.05) and Toll-Like Receptor 4 (p < 0.01) in IPP. Our results suggest beneficial effects of MOS supplementation on gut morphology and the expression of inflammation-related genes in post-weaning piglets, accompanied by increased feed efficiency.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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•Lycopene reduces ≥ G2 skin toxicity frequency in course of panitumumab therapy.•Lycopene prolongs time to appearance of ≥ G2 skin toxicity (p = 0.0007 logrank test)•Lycopene protects ...tissues from oxidative stress due to panitumumab therapy.•Lycopene administration saves antioxidants consumption due to panitumumab therapy.
Epidermal Growth Factor Receptor (EGFR) inhibition leads to the production of reactive oxygen metabolites causing skin inflammatory reactions. Anti-EGFR therapies are frequently associated with skin toxicities which often cause treatment delay and impairment to patient quality of life. Lycopene is a compound in the carotenoid group with an extreme antioxidant action which accumulates in the skin due to its hydrophobic structure. In a pilot study, we describe lactolycopene effectiveness in reducing skin toxicity and protecting tissues from oxidative stress in patients treated with panitumumab. Despite the limited number of patients, we show an absolute reduction of skin grade 2–3 toxicity in 41% of patients and 46% of panitumumab cumulative cycles in the experimental group versus placebo; lactolycopene administration was able to abolish malondialdehyde (MDA) production, a biomarker used to measure lipid peroxidation in the organism, and replenish antioxidant consumption in the course of anti-EGFR therapy.
Trial registration: Clinicaltrials.gov NCT 03,167,268 (Pasto trial).
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