Publications by authors named "Giulia Angelini"

14 Publications

  • Page 1 of 1

Insulin resistance is central to long-term reversal of histologic non-alcoholic steatohepatitis after metabolic surgery.

J Clin Endocrinol Metab 2020 Nov 28. Epub 2020 Nov 28.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Context: Non-alcoholic steatohepatitis(NASH)is considered as the hepatic counterpart of the metabolic syndrome.

Objective: To investigate the determinants of NASH reversal in patients undergoing biliopancreatic diversion(BPD)in a 5-year follow-up study.

Design: Prospective Study, Policlinico Universitario Agostino Gemelli.

Participants: 37 patients underwent fine-needle liver biopsy during BPD. Nine of them had a negative liver biopsy for NASH and were excluded. Ultrasonography-guided percutaneous liver biopsy was obtained at 5 years after operation.

Intervention: Biliopancreatic Diversion and liver biopsy.

Main Outcome Measures: The primary outcome of our study was histologic NASH reversal, at 5-years follow-up. To better characterize the clinical variables involved in the resolution of NASH, we also compared patients without histologic NASH resolution at 5 years, with those in whom NASH had disappeared.

Results: At follow-up, NASH reversed in 56.5% of the patients. NAFLD Activity-Score(NAS)improved from 3.33±1.15 to 1.84±1.10(P<0.0001).Fibrosis reversed in 16% of the patients(P=0.022)and in 32% improved(95% CI, 0.05-0.54).No significant differences in BMI or clinical parameters changes explained the effect of surgery on NASH, apart from the measure insulin sensitivity post-surgery. HOMA-IR decreased from 3.31±1.72 at baseline to 1.73±1.08(P<0.0001)after BPD and Matsuda index improved from 2.66±1.79 to 4.73±3.05(P<0.0001).Lipid profile normalized(total-cholesterol from 4.75±1.18 to 3.32±0.77mmol/l, P<0.0001; LDL-cholesterol from 2.92±0.91 to 1.60±0.51mmol/l, P=0.0001; HDL-cholesterol from 0.97±0.33 to 1.10±0.35mmol/l, P=0.023; triglycerides from 2.52±1.6 to 1.47±0.67 mmol/l, P=0.003).Neural network analysis showed that end-study Matsuda index discriminated between responders and non-responders with high accuracy[receiver operating characteristic curve(ROC)area-under-the curve(AUC)0.98%].

Conclusion: Remission of NASH is driven by reversal of whole-body insulin resistance post-intervention.
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http://dx.doi.org/10.1210/clinem/dgaa892DOI Listing
November 2020

Small intestinal metabolism is central to whole-body insulin resistance.

Gut 2020 Sep 29. Epub 2020 Sep 29.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

Objective: To assess the role of jejunum in insulin resistance in humans and in experimental animals.

Design: Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling.

Results: Whole-body insulin sensitivity (S∙10: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (R) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans.

Conclusion: Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity.

Trial Registration Number: NCT03111953.
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http://dx.doi.org/10.1136/gutjnl-2020-322073DOI Listing
September 2020

Duodenal-jejunal bypass improves nonalcoholic fatty liver disease independently of weight loss in rodents with diet-induced obesity.

Am J Physiol Gastrointest Liver Physiol 2020 10 19;319(4):G502-G511. Epub 2020 Aug 19.

Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Università Cattolica del S. Cuore, Rome, Italy.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver-related mortality. NAFLD is associated with obesity, hepatic fat accumulation, and insulin resistance, all of which contribute to its pathophysiology. Weight-loss is the main therapy for NAFLD, and metabolic surgery is the most effective treatment for morbid obesity and its metabolic comorbidities. Although has been reported that Roux-en-Y gastric bypass can reverse NAFLD, it is unclear whether such effects result from reduced weight, from a lower calorie-intake, or from the direct influence of surgery on mechanisms contributing to NAFLD. We aimed to investigate whether gastrointestinal (GI) bypass surgery could induce direct effects on hepatic fat accumulation and insulin resistance, independently of weight reduction. Twenty Wistar rats on a high-fat diet underwent duodenal-jejunal-bypass (DJB) or sham operation and were pair fed (PF) for 15 wk after surgery to obtain a matched weight. Outcome measures include ectopic fat deposition, expression of genes and proteins involved in fat metabolism, insulin-signaling, and gluconeogenesis in liver and muscle. Despite no differences in body weight and calorie intake, DJB showed lower ectopic fat accumulation, improved peripheral and hepatic insulin sensitivity, and enhanced lipid droplet degradation. In both tissues, DJB increased insulin signaling, whereas hepatic key enzymes involved in gluconeogenesis and de novo lipogenesis were decreased. These findings suggest that DJB can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of NAFLD that share a mutual pathway, in which perilipin-2 (PLIN2) seems to be the main player, supporting further investigation into strategies that target the gut to treat metabolic liver diseases. Our findings suggest that duodenal-jejunal bypass can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of nonalcoholic fatty liver disease that share a mutual pathway, in which perilipin-2 seems to be the main player. Our study supports further investigation into the role of proximal small intestine exclusion in the pathophysiology of nonalcoholic fatty liver disease to uncover less invasive treatments that mimic the effects of metabolic surgery and aims to prevent and treat metabolic liver disease.
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http://dx.doi.org/10.1152/ajpgi.00357.2019DOI Listing
October 2020

Publisher Correction: New insight into the mechanisms of ectopic fat deposition improvement after bariatric surgery.

Sci Rep 2020 Feb 12;10(1):2786. Epub 2020 Feb 12.

Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-58961-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015884PMC
February 2020

The jejunum is the key factor in insulin resistance.

Surg Obes Relat Dis 2020 Apr 3;16(4):509-519. Epub 2020 Jan 3.

Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy.

Background: Biliopancreatic diversion (BPD) is more effective than Roux-en-Y gastric bypass (RYGB) on both insulin resistance and diabetes.

Objectives: Because the major difference between the 2 procedures resides in the length of jejunal bypass, we investigated the role of the jejunum in insulin resistance.

Setting: University hospital in Italy.

Methods: Insulin sensitivity (IS) and secretion were measured before and 4 weeks after RYGB or BPD in 16 patients. A translational study was also conducted in 6 pigs, by isolating a jejunal loop with its vascular and nerve supply (Thiry-Vella loop [TVL]). TVL was doubly stomatized and bowel continuity restored by a side-to-side jejuno-jejunostomy. At baseline and 4 weeks postoperatively a glucose bolus was injected either in the stomach or in the TVL. Whole-body IS and jejunal heat shock proteins (HSPs) were measured. Primary porcine hepatocyte cultures were incubated with plasma or individual HSPs.

Results: Whole-body IS increased from 353.5 ± 26.7 to 442.0 ± 37.4 (P < .05) after RYGB and from 312.4 ± 14.9 to 441.2 ± 15.9 mL/m/min (P < .001) after BPD. Hepatic IS was unchanged after RYGB, while it increased from .3 ± .01 to .4 ± .1 (μM/pM) - 1 (P < .01) after BPD. Total insulin secretion rate remained unchanged after RYGB but decreased (from 58.3 ± 23.6 to 33.1 ± 7.8 nmol/m, P < .05) after BPD. Jejunectomy in pigs enhanced IS (.3 ± .01 versus .2 ± .01 mM/pM, P < .001), while injection of glucose into TVL reduced it (.1 ± .01 versus .3 ± .01 mM/pM, P < .0001). The jejunum secreted HSPs, Hsp70, and GRP78, which impaired insulin signaling in hepatocyte cultures.

Conclusions: This study shows that jejunal bypass in both humans and pigs improves IS. Injection of glucose into the TVL in pigs determines insulin resistance. In response to glucose, the jejunum secretes HSPs that impair insulin signaling.
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http://dx.doi.org/10.1016/j.soard.2019.12.024DOI Listing
April 2020

New insight into the mechanisms of ectopic fat deposition improvement after bariatric surgery.

Sci Rep 2019 11 21;9(1):17315. Epub 2019 Nov 21.

Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy.

Non-alcoholic fatty-liver disease (NAFLD) is frequent in obese patients and represents a major risk factor for the development of diabetes and its complications. Bariatric surgery reverses the hepatic features of NAFLD. However, its mechanism of action remains elusive. We performed a comprehensive analysis of the mechanism leading to the improvement of NAFLD and insulin resistance in both obese rodents and humans following sleeve-gastrectomy (SG). SG improved insulin sensitivity and reduced hepatic and monocyte fat accumulation. Importantly, fat accumulation in monocytes was well comparable to that in hepatocytes, suggesting that Plin2 levels in monocytes might be a non-invasive marker for the diagnosis of NAFLD. Both in vitro and in vivo studies demonstrated an effective metabolic regeneration of liver function and insulin sensitivity. Specifically, SG improved NAFLD significantly by enhancing AMP-activated protein kinase (AMPK) phosphorylation and chaperone-mediated autophagy (CMA) that translate into the removal of Plin2 coating lipid droplets. This led to an increase in lipolysis and specific amelioration of hepatic insulin resistance. Elucidating the mechanism of impaired liver metabolism in obese subjects will help to design new strategies for the prevention and treatment of NAFLD.
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http://dx.doi.org/10.1038/s41598-019-53702-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872729PMC
November 2019

Simulation of gastric bypass effects on glucose metabolism and non-alcoholic fatty liver disease with the Sleeveballoon device.

EBioMedicine 2019 Aug 7;46:452-462. Epub 2019 Aug 7.

Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: Gastric bypass surgery is a very effective treatment of obesity and type 2 diabetes. However, very few eligible patients are offered surgery. Some patients also prefer less invasive approaches. We aimed to study the effects of the Sleeveballoon - a new device combining an intragastric balloon with a connecting sleeve, which covers the duodenal and proximal jejunal mucosa - on insulin sensitivity, glycemic control, body weight and body fat distribution.

Methods: We compared the effects of Sleeveballoon, Roux-en-Y Gastric-Bypass (RYGB) and sham-operation in 30 high-fat diet (HFD) fed Wistar rats. Whole body and hepatic insulin sensitivity and insulin signaling were studied. Transthoracic echocardiography was performed using a Vevo 2100 system (FUJIFILM VisualSonics Inc., Canada). Gastric emptying was measured using gastrografin.

Findings: Hepatic (P = .023) and whole-body (P = .011) insulin sensitivity improved in the Sleeveballoon and RYGB groups compared with sham-operated rats. Body weight reduced in both Sleeveballoon and RYGB groups in comparison to the sham-operated group (503.1 ± 8.9 vs. 614.4 ± 20.6 g, P = .006 and 490.0 ± 17.7 vs. 614.4 ± 20.6 g, P = .006, respectively). Ectopic fat deposition was drastically reduced while glycogen content was increased in both liver and skeletal muscle. Gastric emptying (T) was longer (157.7 ± 29.2 min, P = .007) in the Sleeveballoon than in sham-operated rats (97.1 ± 26.3 min), but shorter in RYGB (3.5 ± 1.1 min, P < .0001). Cardiac function was better in Sleeveballoon and RYGB versus sham-operated rats.

Interpretation: The Sleeveballoon reduces peripheral and hepatic insulin resistance, glycaemia, body weight and ectopic fat deposition to a similar level as RYGB, although the contribution of gastric emptying to blood glucose reduction is different.
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http://dx.doi.org/10.1016/j.ebiom.2019.07.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712366PMC
August 2019

Metabolic surgery improves insulin resistance through the reduction of gut-secreted heat shock proteins.

Commun Biol 2018 13;1:69. Epub 2018 Jun 13.

Department of Internal Medicine, Catholic University, Largo A. Gemelli 8, 00168, Rome, Italy.

Metabolic surgery improves insulin resistance and is associated with the remission of type 2 diabetes, but the mechanisms involved remain unknown. We find that human jejunal mucosa secretes heat shock proteins (HSPs) in vitro, in particular HSP70 and GRP78. Circulating levels of HSP70 are higher in people resistant to insulin, compared to the healthy and normalize after duodenal-jejunal bypass. Insulin sensitivity negatively correlates with the plasma level of HSP70, while body mass index does not. A high-energy diet increases the circulating levels of HSP70 and insulin resistance. HSP70 stimulates the accumulation of lipid droplets and inhibits Ser473 phosphorylation of Akt and glucose uptake in immortalized liver cells and peripheral blood cells. Serum depleted of HSPs, as well as the serum from the insulin-resistant people subjected to a duodenal-jejunal bypass, reverse these features, identifying gut-secreted HSPs as possible causes of insulin resistance. Duodenal-jejunal bypass might reduce the secretion of HSPs either by shortening the food transit or by decreasing the fat stimulation of endocrine cells.
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http://dx.doi.org/10.1038/s42003-018-0069-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123703PMC
June 2018

Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells.

Eur Heart J 2018 04;39(13):1089-1097

Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Largo A. Gemelli, 8-00168 Rome, Italy.

Aims: In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1-5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS.

Methods And Results: To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1-5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1-5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P < 0.001). CD31 domain 1-5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (P = 0.042).

Conclusion: Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1-5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS.
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http://dx.doi.org/10.1093/eurheartj/ehx684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915953PMC
April 2018

Magnetic resonance (MR) features in triple negative breast cancer (TNBC) vs receptor positive cancer (nTNBC).

Clin Imaging 2018 May - Jun;49:12-16. Epub 2017 Oct 27.

Department of Oncology, Biostatistical Consulting, University Hospital S. Chiara, Pisa, Italy.

Few reports in literature describe triple negative breast cancer (TNBC) imaging findings. Aim of the study is to determine MR-features of TNBC compared to receptor positive cancer (nTNBC). From May 2014 to May 2015, we retrospectively enrolled 31 consecutive patients with histological diagnosis of TNBC and a control group of 31 consecutive nTNBC observed in the same period, out of 602 cancer, diagnosed in our department in the same year. Histopathological analysis and MR-features of TNBC (31 patients) were compared to nTNBC (31 patients). MR-features included dimension, fibroglandular tissue (FGT), background parenchimal enhancement (BPE), mass shape, margins, presence of rim, intratumoral signal intensity in T2w, uni-multifocality, kinetic curves. All patients were examined with MR 1,5T (Magnetom Simphony Tim, Siemens Healthcare) performing T2w fat-sat and contrast enhanced high temporal and spatial resolution T1w before and after injection of Gadolinium. 62 staging MR were reviewed. Median age was 50 (30-78ys) with a standard deviation of 10,9. TNBC showed 3 MR features in concordance with current literature: rim enhancement, hyperintensity in T2 sequence and unifocality. Rim enhancement was shown in 67.7% of TNBC (21/31) and 29% of nTNBC (9/31). Higher T2w values were shown in 83.9% of TNBC (26/31) and 58.1% of nTNBC (18/31). Cancer was multifocal in 7/31 (22.6%) of TNBC and 19/31 (61.3%) nTNBC. No correlation was found for dimension (p=0.12), FGT (p=0.959), BPE (p=0.596), homogeneity of enhancement (p=0.43), margins (p=0.671) and kinetic (p=0.37). Multivariate analysis demonstrated that rim enhancement and unifocality correlated independently with TNBC group. Area under ROC curve of our model is 0.835. Furthermore, we evaluated the clinical outcome of all 31 TNBC patients in a follow-up time ranging from 24months to 36months separating them in a free-survival group (23 women) and a recurrence group (8 women with local recurrence or distant metastasis): only kinetic curves resulted to be significantly higher in recurrence group (p=0.042).
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http://dx.doi.org/10.1016/j.clinimag.2017.10.016DOI Listing
September 2018

Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes.

Oncotarget 2017 Mar;8(11):17529-17550

Institute of Cardiology, Catholic University, Rome, Italy.

Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms.Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 μg/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-γ-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P < 0.001). Atorvastatin increased the expression of 2 genes and decreased the expression of 12 genes (in particular, EGR1, FOS,CCR2 and toll like receptor-4; >3-fold changes).The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03).Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.
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http://dx.doi.org/10.18632/oncotarget.15420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392205PMC
March 2017

Human cardiac progenitor cells with regenerative potential can be isolated and characterized from 3D-electro-anatomic guided endomyocardial biopsies.

Int J Cardiol 2017 Aug 1;241:330-343. Epub 2017 Mar 1.

Department of Cardiovascular Medicine, Catholic University of the Sacred Heart, Rome, Italy. Electronic address:

Aims: In the present study, we aimed to develop a percutaneous approach and a reproducible methodology for the isolation and expansion of Cardiac Progenitor Cells (CPCs) from EndoMyocardial Biopsies (EMB) in vivo. Moreover, in an animal model of non-ischemic heart failure (HF), we would like to test whether CPCs obtained by this methodology may engraft the myocardium and differentiate.

Methods And Results: EMB were obtained using a preformed sheath and a disposable bioptome, advanced via right femoral vein in 12 healthy mini pigs, to the right ventricle. EMB were enzymatically dissociated, cells were expanded and sorted for c-kit. We used 3D-Electro-Anatomic Mapping (3D-EAM) to obtain CPCs from 32 patients affected by non-ischemic cardiomyopathy. The in vivo regenerative potential of CPCs was tested in a rodent model of drug-induced non-ischemic cardiomyopathy. c-kit positive CPCs replicative capacity was assessed in 30 patients. Telomere length averaged 7.4±0.4kbp and telomerase activity was present in all preparations (1.7×10 copies). The in situ hybridization experiments showed that injected human CPCs may acquire a neonatal myocyte phenotype given the expression of the alpha-sarcomeric actin together with the presence of the Alu probe, suggesting a beneficial impact on LV performance.

Conclusions: The success in obtaining CPCs characterized by high regenerative potential, in vitro and in vivo, from EMB indicates that harvesting without thoracotomy in patients affected by either ischemic or non-ischemic cardiomyopathy is feasible. These initial results may potentially expand the future application of CPCs to all patients affected by HF not undergoing surgical procedures.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.106DOI Listing
August 2017

PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity.

Oncotarget 2016 Oct;7(41):66386-66397

Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.

Acute promyelocitic leukemia (APL) is characterized by the pathognomonic presence in leukemic blasts of the hybrid protein PML/RARA, that acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid differentiation. Here, we show that primary blasts from APL patients express lower levels of the oncosuppressor protein PTEN, as compared to blast cells from other AML subtypes or normal bone marrow, and demonstrate that PML-RARA directly inhibits PTEN expression. We show that All-Trans Retinoic Acid (ATRA) triggers in APL cells an active chromatin status at the core regulatory region of the PTEN promoter, that allows the binding of the myeloid-regulating transcription factor PU.1, and, in turn, the transcriptional induction of PTEN. ATRA, via PML/RARA degradation, also promotes PTEN nuclear re-localization and decreases expression of the PTEN target Aurora A kinase. In conclusion, our findings support the notion that PTEN is one of the primary targets of PML/RARA in APL.
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http://dx.doi.org/10.18632/oncotarget.11964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341808PMC
October 2016

Insulin Resistance, Microbiota, and Fat Distribution Changes by a New Model of Vertical Sleeve Gastrectomy in Obese Rats.

Diabetes 2016 10 18;65(10):2990-3001. Epub 2016 Jul 18.

Diabetes and Nutritional Sciences, King's College London, London, U.K. Department of Internal Medicine, Catholic University, Rome, Italy

Metabolic surgery improves insulin resistance and type 2 diabetes possibly because of weight loss. We performed a novel sleeve gastrectomy in rats that resects ∼80% of the glandular portion, leaving the forestomach almost intact (glandular gastrectomy [GG]) and compared subsequent metabolic remodeling with a sham operation. GG did not affect body weight, at least after 10 weeks; improved hepatic and peripheral insulin sensitivity likely through increased Akt, glycogen synthase kinase 3, and AMPK phosphorylation; and reduced ectopic fat deposition and hepatic glycogen overaccumulation. Body adipose tissue was redistributed, with reduction of intraabdominal fat. We found a reduction of circulating ghrelin levels, increased GLP-1 plasma concentration, and remodeling of gut microbiome diversity characterized by a lower relative abundance of Ruminococcus and a higher relative abundance of Lactobacillus and Collinsella These data suggest that at least in rat, the glandular stomach plays a central role in the improvement of insulin resistance, even if obesity persists. GG provides a new model of the metabolically healthy obese phenotype.
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http://dx.doi.org/10.2337/db16-0039DOI Listing
October 2016